Methods of treating palmoplantar pustular psoriasis (PPP) using IL-17 antibody

ABSTRACT

The disclosure is directed to methods, treatment regimens, uses, kits and therapies for treating Generalized Pustular Psoriasis (GPP). These methods, treatment regimens, uses, kits and therapies utilize, inter cilia, administration of an IL-17 antagonist, e.g., an IL-17 antibody, such as secukinumab. Additionally disclosed are improved methods for treating plaque-type psoriasis that utilize up-titration and down-titration of the IL-17 antagonist, e.g., an IL-17 antibody, such as secukinumab, as well as modification of dose frequency. Further disclosed are methods of treating palmoplantar pustular psoriasis using the disclosed IL-17 antagonists, e.g., IL-17 antibodies, such as secukinumab.

RELATED APPLICATIONS

The instant application is a continuation of U.S. patent applicationSer. No. 14/911,387, now U.S. Pat. No. 10,434,172, which claims priorityto U.S. Provisional Patent application No. 61/886,242, filed Aug. 15,2013, which is incorporated by reference in its entirety.

TECHNICAL FIELD

The disclosure is directed to methods, treatment regimens, uses, kitsand therapies for treating Generalized Pustular Psoriasis (GPP) byemploying IL-17 antagonists, e.g., IL-17 antibodies.

BACKGROUND OF THE DISCLOSURE

Psoriasis is a chronic relapsing disease of the skin characterized byvariable clinical features. The lesions are classified aserythrosquamous, which indicates that both the vasculature (erythema)and the epidermis (increased scale formation) are involved. Pustularpsoriasis is a variant of psoriasis with sterile pustules presentinglocally or broadly on the skin either acutely, subacutely, orchronically (Camp, RDR (1998) Pustular forms of psoriasis. Textbook ofDermatology, Champion, R H et al eds, Blackwell Science, Oxford;1633-43). Pustular psoriasis is frequently categorized as eithergeneralized pustular psoriasis (GPP) or localized pustular psoriasis(Farber and Nall (1993) Cutis 51:29-32). In generalized pustularpsoriasis, sterile pustules can cover almost the entire body, and in thelocalized form, pustules are confined to isolated locations. GPPincludes von Zumbusch (acute GPP), generalized form of acrodermatitiscontinua (Hallopeau), acute exanthematic, GPP of pregnancy (impetigoherpetiformis), infantile and juvenile GPP, and circinate and annularGPP, whilst localized pustular psoriasis includes chronic and acutepalmoplantar pustulosis. (Farber and Nall, supra; Iizuka et al (2003)Arch Dermatol Res 295:S55-S59).

GPP is a rare form of psoriasis that usually presents as numerousaseptic pustules occurring on reddened skin over the whole body and is apotentially life-threatening systemic inflammatory disease. It isfrequently associated with fever, and involves the formation ofsubcorneal pustules histopathologically characterized by Kogoj'sspongiform pustules. It is characterized by recurrence in periodicepisodes. In the course of the disease, GPP patients may have laboratoryabnormalities associated with systemic inflammation response, frequentlycomplicated with mucosal symptoms and arthritis, and less frequentlywith respiratory failure, eye disease, or secondary amyloidosis. GPP canbe preceded by psoriasis vulgaris (PV). However, this is not always thecase, and recent research shows that GPP that is not preceeded by PV isa distinct subtype of GPP, distinguishable from GPP with PV by adeficiency in the Interleukin 36 Receptor Antagonist (DITRA) due tomutations in IL36RN. (Sugiura et al. (2013) J. Investi. Derm. Acceptedarticle preview 22 May 2013 (doi:10.1038/jid.2013.230)).

A “pustular psoriasis (generalized type) clinical practice guideline”has been published by the Japanese Dermatological Association (IwatsukiK, Terui M, Ozawa A, et al. (2010) Clinical Guidelines for GeneralizedPustular Psoriasis: Therapeutic Guides Incorporating Tumor NecrosisFactor-alpha Inhibitors), presenting information about the diagnosis andthe severity criteria of GPP and recommending therapeutic guides forGPP, as an outcome of a “surveillance study on a rare intractable skindisorder” of the Japan Ministry of Health Labor Welfare (MHLW)Intractable Disease Conquest Research Program. In the guideline,systemic corticosteroids, ciclosporin, etretinate, methotrexate (MTX),and infliximab are recommended as the treatment for GPP. Infliximab, andother biologic drugs targeting TNF-α, have shown some treatment success(see, e.g., Viguier et al. (2012) Arch Dermatol 148:1423-25), as hasustekinumab (see, e.g., Dauden (2010) Br. J. Derm. 163:1346-68).However, only three drugs (ciclosporin, etretinate, and infliximab) areapproved for use in the treatment of pustular psoriasis, and these drugsall have significant limitations. For example, systemic long-termcorticosteroids cause Cushing's syndrome and hypertension, amongst otherside effects. Methotrexate has well-known liver and hematology toxicity.Ciclosporin may be restricted due to its nephrotoxicity after chronicadministration. Etretinate has a very long half-life (about 100 days)and is associated with teratogenicity. Moreover, the oral cavity symptom(including dryness of the mucosa) caused by etretinate often preventsthe continuation of its treatment. For infliximab, it is reported thatthere is loss of response due to the development of neutralizingantibodies (Asahina A (2012) Biologics. Diagnosis, Understanding andTreatment Dermatology Clinical Asset 10 Current Understanding of thePathology and Treatment of Psoriasis; Tokyo: Nakayamashoten, 264-8), andTNF alpha antagonists have the potential to reactivate tuberculosis.

There are fewer therapeutic options available for GPP than for plaquepsoriasis, and those that are available have significant limitations.Hence, broadening the options for the treatment of GPP would address ahigh unmet medical need.

BRIEF SUMMARY OF THE DISCLOSURE

IL-17A is the central lymphokine of a newly defined subset ofinflammatory T cells, the Th17 cells, which are pivotal in severalautoimmune and inflammatory processes. IL-17A neutralization is expectedto treat the underlying pathophysiology of immune mediated disease, andas a consequence provide relief of symptoms. IL-17A is considered toactivate neutrophils, and hence might play an important role in pustularpsoriasis, since the presence of neutrophils in pustules is a typicalfeature of this disease. It has been shown that IL-17 is highlyexpressed in the skin tissue of patients with severe PV and pustularpsoriasis, including both palmoplantar and GPP subgroups (Yilmaz et al.(2012) Arch. Dermatol. Res 304:465-69). However, Yamamoto et al. reportthat, while increased levels of IL-17 in GPP patient's serum isassociated with an increased level of the general inflammatory markerCRP, this increase is not associated with GPP score or levels of whiteblood cells (Yamamoto et al. (2013) Disease Markers 34:153-61). Thus,the role of IL-7 in GPP is not fully understood.

Secukinumab (AIN457) is a high-affinity fully human monoclonalanti-human antibody that inhibits IL-17A activity, which has emerged asa potential treatment for patients with various autoimmune diseases,e.g., rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis,diabetes, asthma, chronic plaque-type psoriasis, and multiple sclerosis.Several Phase II and III studies have shown that secukinumab is superiorto placebo in achievement of PASI 75 in treating chronic plaque-typepsoriasis (e.g., secukinumab 3×150 mg and 3×75 mg were both superior toplacebo in achievement of PASI 75 at Week 12 (81.5% and 57.1%,respectively, vs. 9.1%) in study CAIN457A2220. Secukinumab is currentlyused in global Phase III studies for the treatment of chronicplaque-type psoriasis, and has again shown superiority over placebo, andnewly also over etanercept. International Patent PublicationWO2012/045848 provides dosing regimens for the use of secukinumab totreat psoriasis, but makes no mention of GPP.

Disclosed herein are methods of treating Generalized Pustular Psoriasis(GPP), comprising administering to a patient in need thereof an IL-17antibody or antigen binding fragment thereof, wherein the IL-17 antibodyor antigen binding fragment binds to an epitope of an IL-17 homodimerhaving two mature human IL-17 protein chains, said epitope comprisingLeu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127,Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on theother chain, wherein the IL-17 antibody or antigen binding fragmentthereof has a K_(D) of about 100-about 200 pM (e.g., as determined byBiacore®), and wherein the IL-17 antibody or antigen binding fragmentthereof has an in vivo half-life of about 23-about 30 days.

Disclosed herein are methods of treating GPP, comprising subcutaneouslyadministering an IL-17 antibody or antigen binding fragment thereof to apatient in need thereof as a dose of about 150 mg-about 300 mg withinitial dosing at weeks 0, 1, 2 and 3, followed by monthly dosing,starting at week 4.

Disclosed herein are methods of treating GPP, comprising: a)subcutaneously administering an IL-17 antibody or antigen bindingfragment thereof to a patient in need thereof at a dose of about 150 mgduring weeks 0, 1, 2, 3, and 4; and b) thereafter, subcutaneouslyadministering the IL-17 antibody or antigen binding fragment thereof tothe patient at a dose of about 300 mg during week 8, 9, and 12 and thenmonthly thereafter, beginning during week 16.

Disclosed herein are methods of treating GPP, comprising: a)subcutaneously administering an IL-17 antibody or antigen bindingfragment thereof to a patient in need thereof at a dose of about 150 mgduring weeks 0, 1, 2, 3, and 4; b) assigning the patient to a treatmentassessment based on clinical components of a CGI evaluation administeredduring week 8, wherein assigning a treatment assessment “very muchimproved” or “much improved” provides an indication that no up-titrationis required, and wherein assigning a treatment assessment “worse”, “nochange” or “minimally improved” provides an indication that up-titrationis required; and c) i) thereafter, subcutaneously administering theIL-17 antibody or antigen binding fragment thereof to the patient at adose of about 150 mg monthly, beginning during week 8, if noup-titration is required; or ii) thereafter, subcutaneouslyadministering the IL-17 antibody or antigen binding fragment thereof tothe patient at a dose of about 300 mg during weeks 8, 9 and 12 and thenmonthly thereafter, beginning during week 16, if up-titration isrequired.

Disclosed herein are kits for the treatment of a patient having GPP,comprising: a) a pharmaceutical composition comprising a therapeuticallyeffective amount of an IL-17 antibody or antigen binding fragmentthereof; b) means for administering the IL-17 antibody or antigenbinding fragment thereof to the patient; and c) instructions providing:i) subcutaneously administering the IL-17 antibody or antigen bindingfragment thereof to the patient at a dose of about 150 mg during weeks0, 1, 2, 3, and 4; ii) I) thereafter, subcutaneously administering theIL-17 antibody or antigen binding fragment thereof to the patient at adose of about 150 mg monthly, beginning during week 8; or II)thereafter, subcutaneously administering the IL-17 antibody or antigenbinding fragment thereof to the patient at a dose of about 300 mg duringweeks 8, 9 and 12 and then monthly thereafter, beginning during week 16.

Disclosed herein are kits for the treatment of a patient having GPP,comprising: a) a pharmaceutical composition comprising a therapeuticallyeffective amount of an IL-17 antibody or antigen binding fragmentthereof; b) means for administering the IL-17 antibody or antigenbinding fragment thereof to the patient; and c) instructions providing:i) subcutaneously administering the IL-17 antibody or antigen bindingfragment thereof to the patient at a dose of about 150 mg during weeks0, 1, 2, 3, and 4; ii) assigning the patient to a treatment assessmentbased on clinical components of a CGI evaluation administered duringweek 8, wherein assigning a treatment assessment “very much improved” or“much improved” provides an indication that no up-titration is required,and wherein assigning a treatment assessment “worse”, “no change” or“minimally improved” provides an indication that up-titration isrequired; and iii) I) thereafter, subcutaneously administering the IL-17antibody or antigen binding fragment thereof to the patient at a dose ofabout 150 mg monthly, beginning during week 8, if no up-titration isrequired; or II) thereafter, subcutaneously administering the IL-17antibody or antigen binding fragment thereof to the patient at a dose ofabout 300 mg during weeks 8, 9 and 12 and then monthly thereafter,beginning during week 16, if up-titration is required.

Disclosed herein are IL-17 antibodies or antigen binding fragmentsthereof for use in treating Generalized Pustular Psoriasis (GPP) in apatient in need thereof, characterized in that the IL-17 antibody orantigen binding fragment thereof binds to an epitope of an IL-17homodimer having two mature human IL-17 protein chains, said epitopecomprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126,Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79,Asp80 on the other chain, wherein the IL-17 antibody or antigen bindingfragment thereof has a KD of about 100-about 200 pM (e.g., as determinedby Biacore®), and wherein the IL-17 antibody or antigen binding fragmentthereof has an in vivo half-life of about 23-about 30 days

Disclosed herein are IL-17 antibodies or antigen binding fragmentsthereof for use in treating GPP in a patient in need thereof,characterized in that the IL-17 antibody or antigen binding fragmentthereof is to be subcutaneously administered to the patient as a dose ofabout 150 mg-about 300 mg with initial dosing at weeks 0, 1, 2 and 3,followed by monthly dosing starting at week 4.

Disclosed herein are IL-17 antibodies or antigen binding fragmentsthereof for use in treating GPP in a patient in need thereof,characterized in that the IL-17 antibody or antigen binding fragmentthereof is to be administered to the patient: a) subcutaneously at adose of about 150 mg during weeks 0, 1, 2, 3, and 4; and b) thereafter,subcutaneously at a dose of about 300 mg during week 8, 9, and 12 andthen monthly thereafter, beginning during week 16.

Disclosed herein are IL-17 antibodies or antigen binding fragmentsthereof for use in treating GPP in a patient in need thereof,characterized in that the IL-17 antibody or antigen binding fragmentthereof is to be administered to the patient: a) subcutaneously at adose of about 150 mg during weeks 0, 1, 2, 3, and 4; b) i) thereafter,subcutaneously at a dose of about 150 mg monthly, beginning during week8, if no up-titration is required; or ii) thereafter, subcutaneously ata dose of about 300 mg during weeks 8, 9 and 12 and then monthlythereafter, beginning during week 16, if up-titration is required,wherein prior to step b), the patient is assigned to a treatmentassessment based on clinical components of a CGI evaluation administeredduring week 8, wherein assigning a treatment assessment “very muchimproved” or “much improved” provides an indication that no up-titrationis required, and wherein assigning a treatment assessment “worse”, “nochange” or “minimally improved” provides an indication that up-titrationis required. In preferred embodiments, the disclosed methods, kits anduses employ an IL-17 antibody (e.g., secukinumab or ixekizumab), e.g., ahuman or humanized antibody, most preferably secukinumab.

Additionally disclosed are improved methods for treating plaque-typepsoriasis that utilize up-titration and down-titration of the IL-17antagonist, e.g., an IL-17 antibody, such as secukinumab, as well asmodification of dose frequency. Further disclosed are methods oftreating palmoplantar pustular psoriasis using the disclosed IL-17antagonists, e.g., IL-17 antibodies, such as secukinumab.

Additional methods, regimens, uses, and kits are provided in thefollowing description and appended claims. Further features, advantagesand aspects of the present disclosure will become apparent to thoseskilled in the art from the following description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Provides the clinical trial design for CAIN457A1302.

FIG. 2A shows the percent of the body surface area affected witherythema with pustules for several patients treated with secukinumab instudy CAIN457A1302; the symptoms at baseline (BSL) are set as 100%. Notethat treatment with secukinumab is capable of reducing the severity ofthe key symptom of GPP in a majority of patients. Each line in FIG. 2Arepresents an individual patient profile.

FIG. 2B shows the percent of the body surface area affected witherythema. Note that treatment with secukinumab is capable of reducingthe severity of this key symptom of psoriasis in a majority of patients.Each line in FIG. 2B represents an individual patient profile.

FIG. 3: Provides simulated concentration profiles in plaque-typepsoriasis. Shown are the simulated concentration profiles for the twodose-regimens (150 mg and 300 mg) used in large phase 3 for plaquepsoriasis, plus for the “up-titration” GPP dose-regimen (secukinumab 150mg at baseline [BSL—Week 0], Weeks 1, 2, 3, and 4 and secukinumab 300 mgduring Weeks 8, 9, 12 and 16).

FIG. 4: Provides simulated PASI 75 response rate in plaque psoriasis.Shown are the simulated PASI 75 response rates for the two dose-regimens(150 mg and 300 mg) used in large phase 3 for plaque psoriasis, plus forthe “up-titration” GPP dose-regimen (secukinumab 150 mg at baseline[BSL—Week 0], Weeks 1, 2, 3, and 4 and secukinumab 300 mg during Weeks8, 9, 12 and 16).

FIG. 5: Provides simulated concentration profiles in plaque psoriasis.Shown are the simulated concentration profiles for the two dose-regimens(150 mg and 300 mg) used in phase 3 for plaque psoriasis, plus for two“up-titration” plaque-type psoriasis dose-regimens (secukinumab 150 mgat baseline [BSL—week 0], weeks 1, 2, 3, 4, 8 and secukinumab 300 mgduring week 12 (or week 12 and 13) and week 16).

FIG. 6: Provides simulated time-concentration profiles in plaquepsoriasis. Shown are the simulated concentration profiles of secukinumab(AIN457) for the two dose-regimens (150 mg and 300 mg) used in largephase 3 for plaque psoriasis, plus one “down-titration” plaque-typepsoriasis dose-regimen (secukinumab 300 mg at baseline [BSL—week 0],weeks 1, 2, 3, 4, 8, 12 and secukinumab 150 mg q4 weeks from week 16)plus one regimen with maintenance dosing at every six weeks (secukinumab300 mg at baseline [BSL—week 0], weeks 1, 2, 3, 4, 8, 12 and secukinumab300 mg q6 weeks from week 16).

FIG. 7: Provides simulated PASI90 response rate in plaque psoriasis.Shown are the simulated PASI90 profiles for the two dose-regimens (150mg and 300 mg) used in large phase 3 for plaque psoriasis, plus one“down-titration” plaque-type psoriasis dose-regimen (secukinumab 300 mgat baseline [BSL—week 0], weeks 1, 2, 3, 4, 8, 12 and secukinumab 150 mgq4 weeks from week 16) plus one regimen with maintenance dosing at everysix weeks (secukinumab 300 mg at baseline [BSL—week 0], weeks 1, 2, 3,4, 8, 12 and secukinumab 300 mg q6 weeks from week 16).

DETAILED DESCRIPTION OF THE DISCLOSURE

The term “comprising” encompasses “including” as well as “consisting,”e.g. a composition “comprising” X may consist exclusively of X or mayinclude something additional, e.g., X+Y.

The term “about” in relation to a numerical value x means+/−10% unlessthe context dictates otherwise.

By “monthly” is meant about every 4 weeks (e.g., every 4 weeks), whichis about every 28 days (e.g., every 28 days).

The term “antibody” as referred to herein includes whole antibodies andany antigen-binding portion or single chains thereof. A naturallyoccurring “antibody” is a glycoprotein comprising at least two heavy (H)chains and two light (L) chains inter-connected by disulfide bonds. Eachheavy chain is comprised of a heavy chain variable region (abbreviatedherein as V_(H)) and a heavy chain constant region. The heavy chainconstant region is comprised of three domains, CH1, CH2 and CH3. Eachlight chain is comprised of a light chain variable region (abbreviatedherein as VL) and a light chain constant region. The light chainconstant region is comprised of one domain, CL. The V_(H) and V_(L)regions can be further subdivided into regions of hypervariability,termed hypervariable regions or complementarity determining regions(CDR), interspersed with regions that are more conserved, termedframework regions (FR). Each V_(H) and V_(L) is composed of three CDRsand four FRs arranged from amino-terminus to carboxy-terminus in thefollowing order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variableregions of the heavy and light chains contain a binding domain thatinteracts with an antigen. The constant regions of the antibodies maymediate the binding of the immunoglobulin to host tissues or factors,including various cells of the immune system (e.g., effector cells) andthe first component (C1q) of the classical complement system. In someembodiments of the disclosed methods, regimens, kits, processes, usesand compositions, an antibody to IL-17 or the IL-17 receptor isemployed, preferably an antibody to IL-17, e.g., secukinumab.

The term “antigen-binding portion” of an antibody as used herein, refersto fragments of an antibody that retain the ability to specifically bindto an antigen (e.g., IL-17). It has been shown that the antigen-bindingfunction of an antibody can be performed by fragments of a full-lengthantibody. Examples of binding fragments encompassed within the term“antigen-binding portion” of an antibody include a Fab fragment, amonovalent fragment consisting of the V_(L), V_(H), CL and CH1 domains;a F(ab)2 fragment, a bivalent fragment comprising two Fab fragmentslinked by a disulfide bridge at the hinge region; a Fd fragmentconsisting of the V_(H) and CH1 domains; a Fv fragment consisting of theV_(L) and V_(H) domains of a single arm of an antibody; a dAb fragment(Ward et al., 1989 Nature 341:544-546), which consists of a V_(H)domain; and an isolated CDR. Exemplary antigen binding sites include theCDRs of secukinumab as set forth in SEQ ID NOs:1-6 and 11-13 (Table 4),preferably the heavy chain CDR3. Furthermore, although the two domainsof the Fv fragment, V_(L) and V_(H), are coded for by separate genes,they can be joined, using recombinant methods, by a synthetic linkerthat enables them to be made as a single protein chain in which theV_(L) and V_(H) regions pair to form monovalent molecules (known assingle chain Fv (scFv); see, e.g., Bird et al., 1988 Science242:423-426; and Huston et al., 1988 Proc. Natl. Acad. Sci.85:5879-5883). Such single chain antibodies are also intended to beencompassed within the term “antibody”. Single chain antibodies andantigen-binding portions are obtained using conventional techniquesknown to those of skill in the art. In some embodiments of the disclosedmethods, regimens, kits, processes, uses and compositions, a singlechain antibody or an antigen-binding portion of an antibody againstIL-17 (e.g., secukinumab) or the IL-17 receptor is employed.

An “isolated antibody”, as used herein, refers to an antibody that issubstantially free of other antibodies having different antigenicspecificities (e.g., an isolated antibody that specifically binds IL-17is substantially free of antibodies that specifically bind antigensother than IL-17). The term “monoclonal antibody” or “monoclonalantibody composition” as used herein refer to a preparation of antibodymolecules of single molecular composition. The term “human antibody”, asused herein, is intended to include antibodies having variable regionsin which both the framework and CDR regions are derived from sequencesof human origin. A “human antibody” need not be produced by a human,human tissue or human cell. The human antibodies of the disclosure mayinclude amino acid residues not encoded by human sequences (e.g.,mutations introduced by random or site-specific mutagenesis in vitro, byN-nucleotide addition at junctions in vivo during recombination ofantibody genes, or by somatic mutation in vivo). In some embodiments ofthe disclosed methods, regimens, kits, processes, uses and compositions,the IL-17 antibody is a human antibody, an isolated antibody, and/or amonoclonal antibody.

The term “IL-17” refers to IL-17A, formerly known as CTLA8, and includeswild-type IL-17A from various species (e.g., human, mouse, and monkey),polymorphic variants of IL-17A, and functional equivalents of IL-17A.Functional equivalents of IL-17A according to the present disclosurepreferably have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, oreven 99% overall sequence identity with a wild-type IL-17A (e.g., humanIL-17A), and substantially retain the ability to induce IL-6 productionby human dermal fibroblasts.

The term “K_(D)” is intended to refer to the dissociation rate of aparticular antibody-antigen interaction. The term “K_(D)”, as usedherein, is intended to refer to the dissociation constant, which isobtained from the ratio of K_(d) to K_(a) (i.e. K_(d)/K_(a)) and isexpressed as a molar concentration (M). K_(D) values for antibodies canbe determined using methods well established in the art. A method fordetermining the K_(D) of an antibody is by using surface plasmonresonance, or using a biosensor system such as a Biacore® system. Insome embodiments, the IL-17 antibody or antigen binding fragment thereofbinds human IL-17 with a K_(D) of about 100-250 pM (as measured byBiacore®).

The term “affinity” refers to the strength of interaction betweenantibody and antigen at single antigenic sites. Within each antigenicsite, the variable region of the antibody “arm” interacts through weaknon-covalent forces with antigen at numerous sites; the moreinteractions, the stronger the affinity. Standard assays to evaluate thebinding affinity of the antibodies toward IL-17 of various species areknown in the art, including for example, ELISAs, western blots and RIAs.The binding kinetics (e.g., binding affinity) of the antibodies also canbe assessed by standard assays known in the art, such as by Biacore®analysis.

As used herein, the terms “subject” and “patient” include any human ornonhuman animal. The term “nonhuman animal” includes all vertebrates,e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs,cats, horses, cows, chickens, amphibians, reptiles, etc.

An antibody that “inhibits” one or more of these IL-17 functionalproperties (e.g., biochemical, immunochemical, cellular, physiologicalor other biological activities, or the like) as determined according tomethodologies known to the art and described herein, will be understoodto relate to a statistically significant decrease in the particularactivity relative to that seen in the absence of the antibody (or when acontrol antibody of irrelevant specificity is present). An antibody thatinhibits IL-17 activity affects a statistically significant decrease,e.g., by at least about 10% of the measured parameter, by at least 50%,80% or 90%, and in certain embodiments of the disclosed methods, uses,processes, kits and compositions, the IL-17 antibody used may inhibitgreater than 95%, 98% or 99% of IL-17 functional activity.

“Inhibit IL-6” as used herein refers to the ability of an IL-17 antibody(e.g., secukinumab) to decrease IL-6 production from primary humandermal fibroblasts. The production of IL-6 in primary human (dermal)fibroblasts is dependent on IL-17 (Hwang et al., (2004) Arthritis ResTher; 6:R120-128). In short, human dermal fibroblasts are stimulatedwith recombinant IL-17 in the presence of various concentrations of anIL-17 binding molecule or human IL-17 receptor with Fc part. Thechimeric anti-CD25 antibody Simulect® (basiliximab) may be convenientlyused as a negative control. Supernatant is taken after 16 h stimulationand assayed for IL-6 by ELISA. An IL-17 antibody or antigen bindingfragment thereof as disclosed herein typically has an IC₅₀ forinhibition of IL-6 production (in the presence 1 nM human IL-17) ofabout 50 nM or less (e.g., from about 0.01 to about 50 nM) when testedas above, i.e., said inhibitory activity being measured on IL-6production induced by hu-IL-17 in human dermal fibroblasts. In someembodiments of the disclosed methods, regimens, kits, processes, usesand compositions, the IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab, and functional derivatives thereof have anIC₅₀ for inhibition of IL-6 production as defined above of about 20 nMor less, more preferably of about 10 nM or less, more preferably ofabout 5 nM or less, more preferably of about 2 nM or less, morepreferably of about 1 nM or less.

The term “derivative”, unless otherwise indicated, is used to defineamino acid sequence variants, and covalent modifications (e.g.,pegylation, deamidation, hydroxylation, phosphorylation, methylation,etc.) of an IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab, according to the present disclosure, e.g., of a specifiedsequence (e.g., a variable domain). A “functional derivative” includes amolecule having a qualitative biological activity in common with thedisclosed IL-17 antibodies or antigen binding fragments thereof. Afunctional derivative includes fragments and peptide analogs of an IL-17antibody or antigen binding fragment thereof as disclosed herein.Fragments comprise regions within the sequence of a polypeptideaccording to the present disclosure, e.g., of a specified sequence.Functional derivatives of the IL-17 antibodies or antigen bindingfragments thereof disclosed herein (e.g., functional derivatives ofsecukinumab) preferably comprise V_(H) and/or V_(L) domains that have atleast about 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% overallsequence identity with the V_(H) and/or V_(L) sequences of the IL-17binding molecules disclosed herein (e.g., the V_(H) and/or V_(L)sequences of Table 4), and substantially retain the ability to bindhuman IL-17 or, e.g., inhibit IL-6 production of IL-17 induced humandermal fibroblasts.

The phrase “substantially identical” means that the relevant amino acidor nucleotide sequence (e.g., V_(H) or V_(L) domain) will be identicalto or have insubstantial differences (e.g., through conserved amino acidsubstitutions) in comparison to a particular reference sequence.Insubstantial differences include minor amino acid changes, such as 1 or2 substitutions in a 5 amino acid sequence of a specified region (e.g.,V_(H) or V_(L) domain). In the case of antibodies, the second antibodyhas the same specificity and has at least 50% of the affinity of thesame. Sequences substantially identical (e.g., at least about 85%sequence identity) to the sequences disclosed herein are also part ofthis application. In some embodiments, the sequence identity of aderivative IL-17 antibody (e.g., a derivative of secukinumab, e.g., asecukinumab biosimilar antibody) can be about 90% or greater, e.g., 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher relative to thedisclosed sequences.

“Identity” with respect to a native polypeptide and its functionalderivative is defined herein as the percentage of amino acid residues inthe candidate sequence that are identical with the residues of acorresponding native polypeptide, after aligning the sequences andintroducing gaps, if necessary, to achieve the maximum percent identity,and not considering any conservative substitutions as part of thesequence identity. Neither N- or C-terminal extensions nor insertionsshall be construed as reducing identity. Methods and computer programsfor the alignment are well known. The percent identity can be determinedby standard alignment algorithms, for example, the Basic Local AlignmentSearch Tool (BLAST) described by Altshul et al. ((1990) J. Mol. Biol.,215: 403 410); the algorithm of Needleman et al. ((1970) J. Mol. Biol.,48: 444 453); or the algorithm of Meyers et al. ((1988) Comput. Appl.Biosci., 4: 11 17). A set of parameters may be the Blosum 62 scoringmatrix with a gap penalty of 12, a gap extend penalty of 4, and aframeshift gap penalty of 5. The percent identity between two amino acidor nucleotide sequences can also be determined using the algorithm of E.Meyers and W. Miller ((1989) CABIOS, 4:11-17) which has beenincorporated into the ALIGN program (version 2.0), using a PAM120 weightresidue table, a gap length penalty of 12 and a gap penalty of 4.

“Amino acid(s)” refer to all naturally occurring L-α-amino acids, e.g.,and include D-amino acids. The phrase “amino acid sequence variant”refers to molecules with some differences in their amino acid sequencesas compared to the sequences according to the present disclosure. Aminoacid sequence variants of a polypeptide according to the presentdisclosure, e.g., of a specified sequence, still have the ability tobind the human IL-17 or, e.g., inhibit IL-6 production of IL-17 inducedhuman dermal fibroblasts. Amino acid sequence variants includesubstitutional variants (those that have at least one amino acid residueremoved and a different amino acid inserted in its place at the sameposition in a polypeptide according to the present disclosure),insertional variants (those with one or more amino acids insertedimmediately adjacent to an amino acid at a particular position in apolypeptide according to the present disclosure) and deletional variants(those with one or more amino acids removed in a polypeptide accordingto the present disclosure).

The term “pharmaceutically acceptable” means a nontoxic material thatdoes not interfere with the effectiveness of the biological activity ofthe active ingredient(s).

The term “administering” in relation to a compound, e.g., an IL-17binding molecule or another agent, is used to refer to delivery of thatcompound to a patient by any route.

As used herein, a “therapeutically effective amount” refers to an amountof an IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab, that is effective, upon single or multiple doseadministration to a patient (such as a human) for treating, preventing,preventing the onset of, curing, delaying, reducing the severity of,ameliorating at least one symptom of a disorder or recurring disorder,or prolonging the survival of the patient beyond that expected in theabsence of such treatment. When applied to an individual activeingredient (e.g., an IL-17 antibody, e.g., secukinumab) administeredalone, the term refers to that ingredient alone. When applied to acombination, the term refers to combined amounts of the activeingredients that result in the therapeutic effect, whether administeredin combination, serially or simultaneously.

The term “treatment” or “treat” refer to both prophylactic orpreventative treatment as well as curative or disease modifyingtreatment, including treatment of a patient at risk of contracting thedisease or suspected to have contracted the disease as well as patientswho are ill or have been diagnosed as suffering from a disease ormedical condition, and includes suppression of clinical relapse. Thetreatment may be administered to a patient having a medical disorder orwho ultimately may acquire the disorder, in order to prevent, cure,delay the onset of, reduce the severity of, or ameliorate one or moresymptoms of a disorder or recurring disorder, or in order to prolong thesurvival of a patient beyond that expected in the absence of suchtreatment.

The phrase “therapeutic regimen” means the regimen used to treat anillness, e.g., the dosing protocol used during the treatment of GPP. Atherapeutic regimen may include an induction regimen and a maintenanceregimen.

The phrase “induction regimen” or “induction period” refers to atreatment regimen (or the portion of a treatment regimen) that is usedfor the initial treatment of a disease. In some embodiments, thedisclosed methods, uses, kits, processes and regimens (e.g., methods oftreating GPP) employ an induction regimen. During the treatment of GPP,the first 12 weeks of treatment is generally referred to as the“induction period”, and it is during this time that an induction regimenis employed. While 12 weeks is a traditional induction period forpsoriasis treatment, an induction period may be as short as the first 4weeks of treatment, or as long as the first 16 weeks of treatment. Insome cases, the induction period is the period until maximum efficacy isreached. The general goal of an induction regimen is to provide a highlevel of drug to a patient during the initial period of a treatmentregimen. An induction regimen may employ (in part or in whole) a“loading regimen”, which may include administering a greater dose of thedrug than a physician would employ during maintenance regimen,administering a drug more frequently than a physician would administerthe drug during a maintenance regimen, or both. Dose escalation mayoccur during or after an induction regimen.

The phrase “maintenance regimen” or “maintenance period” refers to atreatment regimen (or the portion of a treatment regimen) that is usedfor the maintenance of a patient during treatment of an illness, e.g.,to keep the patient in remission for long periods of time (months oryears) following the induction period. In some embodiments, thedisclosed methods, uses and regimens employ a maintenance regimen. Amaintenance regimen may employ continuous therapy (e.g., administering adrug at a regular intervals, e.g., weekly, monthly [every 4 weeks],yearly, etc.) or intermittent therapy (e.g., interrupted treatment,intermittent treatment, treatment at relapse, or treatment uponachievement of a particular predetermined criteria [e.g., pain, diseasemanifestation, PASI score, etc.]). Dose escalation may occur during amaintenance regimen.

Measures of GPP disease burden include the Body Surface area Affected(BSA), Japanese Dermatological Association (JDA) severity index for GPP,Clincal Global Impression (CGI) assessment, and/or Psoriasis Area andSeverity Index (PAST). In some embodiments, the BSA, JDA, CGI and/orPASI assessments are employed to show improvement in GPP followingtreatment with the IL-17 antibody (e.g., secukinumab).

In the PASI scoring system, the head, trunk, upper limbs and lower limbsare assessed separately for erythema, thickening (plaque elevation,induration), and scaling (desquamation) as defined in Table 1. Theaverage degree of severity of each sign in each of the four body regionsis assigned a score of 0 to 4. The area covered by lesions on each bodyregion is estimated as a percentage of the total area of that particularbody region. Because the head and neck, upper limbs, trunk and lowerlimbs correspond to approximately 10%, 20%, 30% and 40% of the bodysurface area, respectively, the PASI score is calculated using theformula:PASI=0.1(EH+IH+DH)AH+0.2(EU+IU+DU)AU+0.3(ET+IT+DT)AT+0.4(EL+IL+DL)AL

PASI scores can range from a lower value of 0, corresponding to no signsof psoriasis, up to a theoretic maximum of 72.0. PASI scores may be usedto be specific to a tenth of a point, e.g., 9.0, 10.1, 14.2, 17.3, etc,or rounded to integer numbers. Further information on PASI scoring isavailable in Henseler T, Schmitt-Rau K (2008) Int. J. Dermatol.; 47:1019-1023.

TABLE 1 The PASI Scoring System. Thickening (I) Area score (A) (plaquelevation, Scaling (D) (based on true Body Region Erythema (E)induration) (desquamation) area %)* Head and neck 0 = none 0 = none 0 =none 0 = 0% (H) 1 = slight 1 = slight 1 = slight 1 = 1-9% 2 = moderate 2= moderate 2 = moderate 2 = 10-29% 3 = severe 3 = severe 3 = severe 3 =30-49% 4 = very severe 4 = very severe 4 = very severe 4 = 50-69% 5 =70-89% 6 = 90-100% Upper limbs (U) 0 = none 0 = none 0 = none 0 = 0% 1 =slight 1 = slight 1 = slight 1 = 1-9% 2 = moderate 2 = moderate 2 =moderate 2 = 10-29% 3 = severe 3 = severe 3 = severe 3 = 30-49% 4 = verysevere 4 = very severe 4 = very severe 4 = 50-69% 5 = 70-89% 6 = 90-100%Trunk, axillae and 0 = none 0 = none 0 = none 0 = 0% groin (T) 1 =slight 1 = slight 1 = slight 1 = 1-9% 2 = moderate 2 = moderate 2 =moderate 2 = 10-29% 3 = severe 3 = severe 3 = severe 3 = 30-49% 4 = verysevere 4 = very severe 4 = very severe 4 = 50-69% 5 = 70-89% 6 = 90-100%Lower limbs and 0 = none 0 = none 0 = none 0 = 0% buttocks (L) 1 =slight 1 = slight 1 = slight 1 = 1-9% 2 = moderate 2 = moderate 2 =moderate 2 = 10-29% 3 = severe 3 = severe 3 = severe 3 = 30-49% 4 = verysevere 4 = very severe 4 = very severe 4 = 50-69% 5 = 70-89% 6 = 90-100%

The following PASI definitions are used according to Committee formedicinal products for human use (CHMP), European Medicines Agency forthe Evaluation of Medicines for Human Use. (2004) Guideline on clinicalinvestigation of medicinal products indicated for the treatment ofpsoriasis. CHMP/EWP/2454/02 corr document. London, UK:

-   -   Treatment response (responder): Patients achieving ≥75%        improvement (reduction) in Psoriasis Area and Severity Index        (PAST) score compared to baseline (also referred to as PASI 75)        are defined as treatment responders.    -   Partial response (partial responder): Patients achieving a ≥50%        improvement from baseline PASI score (also referred to as        PASI 50) but less than 75% (also referred to as PASI 75) are        defined as partial responders.    -   Non response (non-responder): Patients achieving a PASI        reduction of <50% from baseline PASI score are defined as        non-responders.    -   Relapse (relapser): If patients loose ≥50% of the PASI gain        achieved during the previous time in the study, patients will be        regarded as having a “relapse”.    -   Rebound (rebounder): Worsening of the value at baseline PASI (or        new pustular, erythrodermic or more inflammatory psoriasis        occurring within 8 weeks of stopping therapy), e.g., a PASI        of >125% of the value at baseline PASI.

The JDA severity index rating scale for GPP is shown in Table 2:

TABLE 2 JDA Severeity Index for GPP (JDA severity Index for GPP; totalscore 0-17. Assessment of skin lesions: area of erythema with pustules,area of erythema, and area of edema; each score 0-3. Assessment ofsystemic manifestations and laboratory findings: fever, WBC count, CRPand serum albumin; each score 0-2). Score 0 1 2 3 Assessment of skinlesions Area of erythema with 0% >0%, <10% ≥10%, <50% ≥50% pustules*Area of erythema (total)* 0% >0%, <25% ≥25%, <75% ≥75% Area of edema*0% >0%, <10% ≥10%, <50% ≥50% Assessment of systemic manifestations andlaboratory findings Fever (° C.) <37 ≥37, <38.5 ≥38.5 — WBC count (μl)<10,000 ≥10,000, ≥15,000 — <15,000 CRP (mg/dl) <0.3 ≥0.3, <7 ≥7 — Serumalbumin (g/dl) ≥3.8 <3.8, ≥3 <3 — Severity index (severity score): 1-6 =mild; 7-10 = moderate; 11-17 = severe *Percentage of overall bodysurface area

The JDA severity index for GPP is derived as indicated in Table 2. Areaof erythema with pustules, area of erythema (total), area of edema,fever, WBC, hsCRP and serum albumin are assessed separately. The totalscore of JDA severity index for GPP is assigned a score of 0-17. Thepercentage of affected overall body surface area is assessed for eachsymptom (erythema; erythema with pustules) using the palm method (whereone palm of the subject equals 1% [one percent] of the overall bodysurface). The JDA severity index is a standardized and validatedmeasurement for GPP in Japan (Iwatsuki et al. (2010), supra; Iwatsuki etal. (2010) Jpn. J. Dermatol. 120:815-839; see also Yamamoto et al.(2013) Disease Markers 34:153-161). In some embodiments, prior totreatment with the IL-17 antibody or antigen binding fragment thereof,the GPP patient has erythema area with pustule ≥10%.

The total Body Surface area Affected (BSA) by psoriasis is estimatedfrom the percentages of areas affected by psoriasis, including head,trunk, upper limbs and lower limbs (see above for PASI assessment). Eachreported percentage will be multiplied by its respective body regioncorresponding factor (head=0.1, trunk=0.3, upper limbs=0.2, lowerlimbs=0.4). The resulting four percentages will be added up to estimatethe total BSA by psoriasis. In some embodiments, prior to treatment withthe IL-17 antibody or antigen binding fragment thereof, the GPP patienthas greater than at least 1% BSA by GPP, greater than at least 5% BSA byGPP, greater than at least 10% BSA by GPP, greater than at least 25% BSAby GPP, or greater than at least 50% BSA by GPP.

The Clinical Global Impression (CGI) assessment is conducted asindicated in Table 3. CGI is evaluated based on the change of the totalscore of JDA severity index for GPP at a given visit, relative tobaseline (BSL).

TABLE 3 CGI assessment. Change of total score of and/ JDA severity indexfor GPP or Other reference Very much improved reduction by three pointsor or Clear or almost clear of signs of GPP more Much improved reductionby one or two or At least one of the following: points Erythema areawith pustules (%) reduced by ≤30% compared to BSL* or Clinicallymeaningful improvement in at least two other components of the JDAseverity index for GPP (erythema area, edema area, Fever, WBC, CRP, Alb)Minimally improved 0 points (No change) and At least one of thefollowing: Erythema area with pustules (%) reduced by ≤20% compared toBSL* or Clinically meaningful improvement in at least one othercomponent of the JDA severity index for GPP (erythema area, edema area,Fever, WBC, CRP, Alb) No change 0 points (No change) and Not meeting theother criteria of “minimally improved” Worsened ≥+1 point — Notapplicable

The phrase “means for administering” is used to indicate any availableimplement for systemically administering a drug to a patient, including,but not limited to, a pre-filled syringe, a vial and syringe, aninjection pen, an autoinjector, an i.v. drip and bag, a pump, a patchpump, etc. With such items, a patient may self-administer the drug(i.e., administer the drug on their own behalf) or a physician mayadminister the drug. Typically, dosages given in “mg/kg” areadministered via an i.v. route, and doses given in “mg” are administeredvia i.m. or s.c. injections. In some embodiments of the disclosedmethods, kits, regimens and uses, the IL-17 antibody or antigen bindingfragment thereof, e.g., secukinumab, is delivered to the patient via thei.v. route. In some embodiments of the disclosed methods, kits, regimensand uses, the IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab, is delivered to the patient via the s.c. route.

“Generalized Pustular Psoriasis” and “GPP” refers to a variant ofpustular psoriasis characterized by fever, chills, rigors andgeneralized pustule (histopahologically characterized by Kogoj'sspongiform pustules) formation of the skin (Iizuka et al (2003) ArchDermatol Res 295:S55-S59). GPP includes von Zumbusch (acute GPP),generalized form of acrodermatitis continua (Hallopeau), acuteexanthematic GPP of pregnancy (impetigo herpetiformis), infantile andjuvenile GPP, and circinate annular GPP (Farber and Nall, supra; Iizukaet al., supra). In some embodiments of the disclosed methods, kits,regimens and uses, the patient has von Zumbusch GPP, generalized form ofacrodermatitis continua (Hallopeau), acute exanthematic, GPP ofpregnancy (impetigo herpetiformis), infantile or juvenile GPP, orcircinate annular GPP.

GPP can occur in patients with a history of ordinary psoriasis(psoriasis vulgaris) (“GPP with psoriasis vulgaris”) and in patientswithout any history of ordinary psoriasis (“GPP without psoriasisvulgaris”) (Iizuka et al. supra). In some embodiments of the disclosedmethods, kits, regimens and uses, the patient has GPP with PV. In otherembodiments, the patient has GPP without PV.

It has recently been determined that the majority of patients having GPPwithout PV have a deficiency of Interleukin-36 Receptor Antagonistprotein found in their epidermis, resulting from homozygous orcompound-heterozygous IL36RN mutations (Sugiura et al., supra). In someembodiments of the disclosure, the patient has a decreased level ofInterleukin-36 Receptor Antagonist (e.g., mRNA or protein) in the skinrelative to a subject not having GPP. In some embodiments of thedisclosure, the patient is selected for treatment with the IL-17antibody or antigen binding fragment thereof (e.g., secukinumab) basedon having been previously determined to have a decreased level ofInterleukin-36 Receptor Antagonist (mRNA or protein) in the skinrelative to a subject not having GPP.

Yamamoto et al. (2013), supra have determined that IL-10 and IL-22 aresignificantly decreased in serum of GPP patients in parallel with theirGPP score, making these two serum cytokines useful to evalue theefficacy of treatment for GPP. In some embodiments of the disclosedmethods, kits, regimens and uses, a decrease in the level of IL-10and/or level of IL-22 is used to assess improvement in GPP score inresponse to treatment with an IL-17 antibody or antigen binding fragmentthereof (e.g., secukinumab).

IL-17 Antibodies and Antigen Binding Fragments Thereof

The various disclosed pharmaceutical compositions, regimens, processes,uses, methods and kits utilize an IL-17 antibody or antigen bindingfragment thereof, e.g., secukinumab.

In one embodiment, the IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab, comprises at least one immunoglobulin heavychain variable domain (V_(H)) comprising hypervariable regions CDR1,CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:1,said CDR2 having the amino acid sequence SEQ ID NO:2, and said CDR3having the amino acid sequence SEQ ID NO:3. In one embodiment, the IL-17antibody or antigen binding fragment thereof, e.g., secukinumab,comprises at least one immunoglobulin light chain variable domain(V_(L)) comprising hypervariable regions CDR1′, CDR2′ and CDR3′, saidCDR1′ having the amino acid sequence SEQ ID NO:4, said CDR2′ having theamino acid sequence SEQ ID NO:5 and said CDR3′ having the amino acidsequence SEQ ID NO:6. In one embodiment, the IL-17 antibody or antigenbinding fragment thereof, e.g., secukinumab, comprises at least oneimmunoglobulin heavy chain variable domain (V_(H)) comprisinghypervariable regions CDR1-x, CDR2-x and CDR3-x, said CDR1-x having theamino acid sequence SEQ ID NO:11, said CDR2-x having the amino acidsequence SEQ ID NO:12, and said CDR3-x having the amino acid sequenceSEQ ID NO:13.

In one embodiment, the IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab, comprises at least one immunoglobulin V_(H)domain and at least one immunoglobulin V_(L) domain, wherein: a) theimmunoglobulin V_(H) domain comprises (e.g., in sequence): i)hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the aminoacid sequence SEQ ID NO:1, said CDR2 having the amino acid sequence SEQID NO:2, and said CDR3 having the amino acid sequence SEQ ID NO:3; orii) hypervariable regions CDR1-x, CDR2-x and CDR3-x, said CDR1-x havingthe amino acid sequence SEQ ID NO:11, said CDR2-x having the amino acidsequence SEQ ID NO:12, and said CDR3-x having the amino acid sequenceSEQ ID NO:13; and b) the immunoglobulin V_(L) domain comprises (e.g., insequence) hypervariable regions CDR1′, CDR2′ and CDR3′, said CDR1′having the amino acid sequence SEQ ID NO:4, said CDR2′ having the aminoacid sequence SEQ ID NO:5, and said CDR3′ having the amino acid sequenceSEQ ID NO:6.

In one embodiment, the IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab, comprises: a) an immunoglobulin heavy chainvariable domain (V_(H)) comprising the amino acid sequence set forth asSEQ ID NO:8; b) an immunoglobulin light chain variable domain (V_(L))comprising the amino acid sequence set forth as SEQ ID NO:10; c) animmunoglobulin V_(H) domain comprising the amino acid sequence set forthas SEQ ID NO:8 and an immunoglobulin V_(L) domain comprising the aminoacid sequence set forth as SEQ ID NO:10; d) an immunoglobulin V_(H)domain comprising the hypervariable regions set forth as SEQ ID NO:1,SEQ ID NO:2, and SEQ ID NO:3; e) an immunoglobulin V_(L) domaincomprising the hypervariable regions set forth as SEQ ID NO:4, SEQ IDNO:5 and SEQ ID NO:6; f) an immunoglobulin V_(H) domain comprising thehypervariable regions set forth as SEQ ID NO:11, SEQ ID NO:12 and SEQ IDNO:13; g) an immunoglobulin V_(H) domain comprising the hypervariableregions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 and animmunoglobulin V_(L) domain comprising the hypervariable regions setforth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; or h) animmunoglobulin V_(H) domain comprising the hypervariable regions setforth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13 and animmunoglobulin V_(L) domain comprising the hypervariable regions setforth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6.

For ease of reference the amino acid sequences of the hypervariableregions of the secukinumab monoclonal antibody, based on the Kabatdefinition and as determined by the X-ray analysis and using theapproach of Chothia and coworkers, is provided in Table 4, below.

TABLE 4 Amino acid sequences of the hypervariable regionsof the secukinumab monoclonal antibodies. Light-Chain CDR1′ KabatR-A-S-Q-S-V-S-S-S-Y-L-A (SEQ ID NO: 4) ChothiaR-A-S-Q-S-V-S-S-S-Y-L-A (SEQ ID NO: 4) CDR2′ KabatG-A-S-S-R-A-T (SEQ ID NO: 5) Chothia G-A-S-S-R-A-T (SEQ ID NO: 5) CDR2′Kabat Q-Q-Y-G-S-S-P-C-T (SEQ ID NO: 6) ChothiaQ-Q-Y-G-S-S-P-C-T (SEQ ID NO: 6) Heavy-Chain CDR1 KabatN-Y-W-M-N (SEQ ID NO: 1) CDR1-x ChothiaG-F-T-F-S-N-Y-W-M-N (SEQ ID NO: 11) CDR2 KabatA-I-N-Q-D-G-S-E-K-Y-Y-V-G-S-V-K-G (SEQ ID NO: 2) CDR2-x ChothiaA-I-N-Q-D-G-S-E-K-Y-Y (SEQ ID NO: 12) CDR3 KabatD-Y-Y-D-I-L-T-D-Y-Y-I-H-Y-W-Y-F-D-L (SEQ ID NO: 3) CDR3-x ChothiaC-V-R-D-Y-Y-D-I-L-T-D-Y-Y-I-H-Y-W- Y-F-D-L-W-G (SEQ ID NO: 13)

In preferred embodiments, the constant region domains preferably alsocomprise suitable human constant region domains, for instance asdescribed in “Sequences of Proteins of Immunological Interest”, Kabat E.A. et al, US Department of Health and Human Services, Public HealthService, National Institute of Health. The DNA encoding the VL ofsecukinumab is set forth in SEQ ID NO:9. The DNA encoding the VH ofsecukinumab is set forth in SEQ ID NO:7.

In some embodiments, the IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab, comprises the three CDRs of SEQ ID NO:10. Inother embodiments, the IL-17 antibody comprises the three CDRs of SEQ IDNO:8. In other embodiments, the IL-17 antibody comprises the three CDRsof SEQ ID NO:10 and the three CDRs of SEQ ID NO:8. CDRs of SEQ ID NO:8and SEQ ID NO:10, according to both the Chothia and Kabat definition,may be found in Table 4.

In some embodiments, the IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab, comprises the light chain of SEQ ID NO:15.In other embodiments, the IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab, comprises the heavy chain of SEQ ID NO:17.In other embodiments, the IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab, comprises the light chain of SEQ ID NO:15and the heavy domain of SEQ ID NO:17. In some embodiments, the IL-17antibody or antigen binding fragment thereof, e.g., secukinumab,comprises the three CDRs of SEQ ID NO:15. In other embodiments, theIL-17 antibody or antigen binding fragment thereof, e.g., secukinumab,comprises the three CDRs of SEQ ID NO:17. In other embodiments, theIL-17 antibody or antigen binding fragment thereof, e.g., secukinumab,comprises the three CDRs of SEQ ID NO:15 and the three CDRs of SEQ IDNO:17. CDRs of SEQ ID NO:15 and SEQ ID NO:17, according to both theChothia and Kabat definition, may be found in Table 4. The DNA encodingthe light chain of secukinumab is set forth as SEQ ID NO:14. The DNAencoding the heavy chain of secukinumab is set forth as SEQ ID NO:16.

Hypervariable regions may be associated with any kind of frameworkregions, though preferably are of human origin. Suitable frameworkregions are described in Kabat E. A. et al, ibid. The preferred heavychain framework is a human heavy chain framework, for instance that ofthe secukinumab antibody. It consists in sequence, e.g. of FR1 (aminoacid 1 to 30 of SEQ ID NO:8), FR2 (amino acid 36 to 49 of SEQ ID NO:8),FR3 (amino acid 67 to 98 of SEQ ID NO:8) and FR4 (amino acid 117 to 127of SEQ ID NO:8) regions. Taking into consideration the determinedhypervariable regions of secukinumab by X-ray analysis, anotherpreferred heavy chain framework consists in sequence of FR1-x (aminoacid 1 to 25 of SEQ ID NO:8), FR2-x (amino acid 36 to 49 of SEQ IDNO:8), FR3-x (amino acid 61 to 95 of SEQ ID NO:8) and FR4 (amino acid119 to 127 of SEQ ID NO:8) regions. In a similar manner, the light chainframework consists, in sequence, of FR1′ (amino acid 1 to 23 of SEQ IDNO:10), FR2′ (amino acid 36 to 50 of SEQ ID NO:10), FR3′ (amino acid 58to 89 of SEQ ID NO:10) and FR4′ (amino acid 99 to 109 of SEQ ID NO:10)regions.

In one embodiment, the IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab, is selected from a human anti IL-17 antibodywhich comprises at least: a) an immunoglobulin heavy chain or fragmentthereof which comprises a variable domain comprising, in sequence, thehypervariable regions CDR1, CDR2 and CDR3 and the constant part orfragment thereof of a human heavy chain; said CDR1 having the amino acidsequence SEQ ID NO:1, said CDR2 having the amino acid sequence SEQ IDNO:2, and said CDR3 having the amino acid sequence SEQ ID NO:3; and b)an immunoglobulin light chain or fragment thereof which comprises avariable domain comprising, in sequence, the hypervariable regionsCDR1′, CDR2′, and CDR3′ and the constant part or fragment thereof of ahuman light chain, said CDR1′ having the amino acid sequence SEQ ID NO:4, said CDR2′ having the amino acid sequence SEQ ID NO:5, and said CDR3′having the amino acid sequence SEQ ID NO:6.

In one embodiment, the IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab, is selected from a single chain bindingmolecule which comprises an antigen binding site comprising: a) a firstdomain comprising, in sequence, the hypervariable regions CDR1, CDR2 andCDR3, said CDR1 having the amino acid sequence SEQ ID NO:1, said CDR2having the amino acid sequence SEQ ID NO:2, and said CDR3 having theamino acid sequence SEQ ID NO:3; and b) a second domain comprising, insequence, the hypervariable regions CDR1′, CDR2′ and CDR3′, said CDR1′having the amino acid sequence SEQ ID NO:4, said CDR2′ having the aminoacid sequence SEQ ID NO:5, and said CDR3′ having the amino acid sequenceSEQ ID NO:6; and c) a peptide linker which is bound either to theN-terminal extremity of the first domain and to the C-terminal extremityof the second domain or to the C-terminal extremity of the first domainand to the N-terminal extremity of the second domain.

Alternatively, the IL-17 antibody or antigen binding fragment thereof,e.g., secukinumab, for use in the disclosed methods may comprise aderivative of the molecules set forth herein by sequence (e.g., apegylated version of secukinumab). Alternatively, the V_(H) or V_(L)domain of the IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab, for use in the disclosed methods may have V_(H) or V_(L)domains that are substantially identical to the V_(H) or V_(L) domainsset forth herein (e.g., those set forth in SEQ ID NO:8 and 10). A humanIL-17 antibody disclosed herein may comprise a heavy chain that issubstantially identical to that set forth as SEQ ID NO:17 and/or a lightchain that is substantially identical to that set forth as SEQ ID NO:15.A human IL-17 antibody disclosed herein may comprise a heavy chain thatcomprises SEQ ID NO:17 and a light chain that comprises SEQ ID NO:15. Ahuman IL-17 antibody disclosed herein may comprise: a) one heavy chainwhich comprises a variable domain having an amino acid sequencesubstantially identical to that shown in SEQ ID NO:8 and the constantpart of a human heavy chain; and b) one light chain which comprises avariable domain having an amino acid sequence substantially identical tothat shown in SEQ ID NO:10 and the constant part of a human light chain.Alternatively, the IL-17 antibody or antigen binding fragment thereof,e.g., secukinumab, for use in the disclosed methods may be an amino acidsequence variant of the reference molecules set forth herein. In allsuch cases of derivative and variants, the IL-17 antibody or antigenbinding fragment thereof, e.g., secukinumab, is capable of inhibitingthe activity of about 1 nM (=30 ng/ml) human IL-17 at a concentration ofabout 50 nM or less, about 20 nM or less, about 10 nM or less, about 5nM or less, about 2 nM or less, or more preferably of about 1 nM or lessof said molecule by 50%, said inhibitory activity being measured on IL-6production induced by hu-IL-17 in human dermal fibroblasts.

The inhibition of the binding of IL-17 to its receptor may beconveniently tested in various assays including such assays as describedin WO 2006/013107. By the term “to the same extent” is meant that thereference and the derivative molecules exhibit, on a statistical basis,essentially identical IL-17 inhibitory activity in one of the assaysreferred to herein (see Example 1 of WO 2006/013107). For example, theIL-17 antibody or antigen binding fragment thereof disclosed hereintypically have IC₅₀s for the inhibition of human IL-17 on IL-6production induced by human IL-17 in human dermal fibroblasts which arebelow about 10 nM, more preferably about 9, 8, 7, 6, 5, 4, 3, 2, orabout 1 nM of that of, preferably substantially the same as, the IC₅₀ ofthe corresponding reference molecule when assayed as described inExample 1 of WO 2006/013107. Alternatively, the assay used may be anassay of competitive inhibition of binding of IL-17 by soluble IL-17receptors (e.g. the human IL-17 R/Fc constructs of Example 1 of WO2006/013107) and the IL-17 antibodies or antigen binding fragmentsthereof of the disclosure.

The disclosure also includes IL-17 antibodies or antigen bindingfragments thereof, e.g., secukinumab, in which one or more of the aminoacid residues of the V_(H) or V_(L) domain, typically only a few (e.g.,1-10), are changed relative to the V_(H) or V_(L) domain set forth asSEQ ID NO:8 and SEQ ID NO:10; for instance by mutation, e.g., sitedirected mutagenesis of the corresponding DNA sequences. The disclosureincludes the DNA sequences coding for such changed IL-17 antibodies.

The disclosure also includes IL-17 antibodies or antigen bindingfragments thereof, e.g., secukinumab, that have binding specificity forhuman IL-17, in particular IL-17 antibodies capable of inhibiting thebinding of IL-17 to its receptor and IL-17 antibodies capable ofinhibiting the activity of 1 nM (=30 ng/ml) human IL-17 at aconcentration of about 50 nM or less, about 20 nM or less, about 10 nMor less, about 5 nM or less, about 2 nM or less, or more preferably ofabout 1 nM or less of said molecule by 50% (said inhibitory activitybeing measured on IL-6 production induced by hu-IL-17 in human dermalfibroblasts).

In some embodiments, the IL-17 antibody, e.g., secukinumab, binds to anepitope of mature human IL-17 comprising Leu74, Tyr85, His86, Met87,Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129. In someembodiments, the IL-17 antibody, e.g., secukinumab, binds to an epitopeof mature human IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80. Insome embodiments, the IL-17 antibody, e.g., secukinumab, binds to anepitope of an IL-17 homodimer having two mature human IL-17 chains, saidepitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125,Pro126, Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46,Ala79, Asp80 on the other chain. The residue numbering scheme used todefine these epitopes is based on residue one being the first amino acidof the mature protein (ie., IL-17A lacking the 23 amino acid N-terminalsignal peptide and beginning with Glycine). The sequence for immatureIL-17A is set forth in the Swiss-Prot entry Q16552. In some embodiments,the IL-17 antibody has a K_(D) of about 100-200 pM, e.g., as measured byBiacore®. In some embodiments, the IL-17 antibody has an IC₅₀ of about0.4 nM for in vitro neutralization of the biological activity of about0.67 nM human IL-17A. In some embodiments, the absolute bioavailabilityof subcutaneously (s.c.) administered IL-17 antibody has a range ofabout 60-about 80%, e.g., about 76%. In some embodiments, the IL-17antibody, such as secukinumab, has an elimination half-life of about 4weeks (e.g., about 23 to about 35 days, about 23 to about 30 days, e.g.,about 30 days). In some embodiments, the IL-17 antibody, such assecukinumab, has a T_(max) of about 7-8 days.

Particularly preferred IL-17 antibodies or antigen binding fragmentsthereof, e.g., secukinumab, for use in the disclosed methods, uses,kits, etc. are human antibodies, especially secukinumab as described inExamples 1 and 2 of WO 2006/013107 (U.S. Pat. No. 7,807,155, which isincorporated by reference herein in its entirety). Secukinumab is arecombinant high-affinity, fully human monoclonal anti-humaninterleukin-17A (IL-17A, IL-17) antibody of the IgG1/kappa isotype thatis currently in clinical trials for the treatment of immune-mediatedinflammatory conditions. Secukinumab (see, e.g., WO2006/013107 andWO2007/117749) has a very high affinity for IL-17, i.e., a K_(D) ofabout 100-200 pM (e.g., as measured by Biacore®) and an IC₅₀ for invitro neutralization of the biological activity of about 0.67 nM humanIL-17A of about 0.4 nM. Thus, secukinumab inhibits antigen at a molarratio of about 1:1. This high binding affinity makes the secukinumabantibody particularly suitable for therapeutic applications.Furthermore, it has been determined that secukinumab has a very longhalf life, i.e., about 4 weeks, which allows for prolonged periodsbetween administration, an exceptional property when treating chroniclife-long disorders, such as psoriasis.

Other IL-17 antagonists (e.g., IL-17 antibodies, IL-17 receptor decoys,and IL-17 receptor antibodies) for use in the disclosed methods, kitsand uses are those set forth in U.S. Pat. Nos. 8,057,794; 8,003,099;8,110,191; and 7,838,638; International Patent Publication WO13011368and US Published Patent Application Nos: 20120034656 and 20110027290.

Regimens, Methods of Treatment and Uses

Generalized Pustular Psoriasis (GPP)

It will be understood that IL-17 antibodies or antigen binding fragmentsthereof, e.g., secukinumab, are useful for the treatment, prevention, oramelioration of GPP.

The IL-17 antibodies or antigen binding fragments thereof, e.g.,secukinumab, may be used in vitro, ex vivo, or incorporated intopharmaceutical compositions and administered to individuals (e.g., humanpatients) in vivo to treat, ameliorate, or prevent GPP. A pharmaceuticalcomposition will be formulated to be compatible with its intended routeof administration (e.g., oral compositions generally include an inertdiluent or an edible carrier). Other nonlimiting examples of routes ofadministration include parenteral (e.g., intravenous), intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical),transmucosal, and rectal administration. The pharmaceutical compositionscompatible with each intended route are well known in the art.

The IL-17 antibodies or antigen binding fragments thereof, e.g.,secukinumab, may be used as a pharmaceutical composition when combinedwith a pharmaceutically acceptable carrier. Such a composition maycontain, in addition to an IL-17 antibodies or antigen binding fragmentsthereof, e.g., secukinumab, carriers, various diluents, fillers, salts,buffers, stabilizers, solubilizers, and other materials well known inthe art. The characteristics of the carrier will depend on the route ofadministration. The pharmaceutical compositions for use in the disclosedmethods may also contain additional therapeutic agents for treatment ofthe particular targeted disorder. For example, a pharmaceuticalcomposition may also include anti-inflammatory agents. Such additionalfactors and/or agents may be included in the pharmaceutical compositionto produce a synergistic effect with the IL-17 binding molecules, or tominimize side effects caused by the IL-17 antibodies or antigen bindingfragments thereof, e.g., secukinumab.

Pharmaceutical compositions for use in the disclosed methods may bemanufactured in conventional manner. The use of antibodies as the activeingredient of pharmaceuticals is now widespread, including the productsHerceptin® (trastuzumab), Rituxan® (rituximab), Synagis® (palivizumab),etc. Techniques for lyophilisation, preparation of aqueous formulations,and purification of antibodies to a pharmaceutical grade are well knownin the art.

Antibodies, e.g., antibodies to IL-17, are typically formulated eitherin aqueous form ready for parenteral administration or as lyophilisatesfor reconstitution with a suitable diluent prior to administration. Insome embodiments of the disclosed methods and uses, the IL-17 antibody,e.g., secukinumab, is formulated as a lyophilisate. Suitablelyophilisate formulations can be reconstituted in a small liquid volume(e.g., 2 ml or less) to allow subcutaneous administration and canprovide solutions with low levels of antibody aggregation. For immediateadministration it is dissolved in a suitable aqueous carrier, forexample sterile water for injection or sterile buffered physiologicalsaline. If it is considered desirable to make up a solution of largervolume for administration by infusion rather than a bolus injection, maybe advantageous to incorporate human serum albumin or the patient's ownheparinised blood into the saline at the time of formulation. Thepresence of an excess of such physiologically inert protein preventsloss of antibody by adsorption onto the walls of the container andtubing used with the infusion solution. If albumin is used, a suitableconcentration is from 0.5 to 4.5% by weight of the saline solution.

In some embodiments of the disclosed methods and uses, the IL-17antibody, e.g., secukinumab, is provided in aqueous forms for immediateuse.

When a therapeutically effective amount of an IL-17 antibody or antigenbinding fragment thereof, e.g., secukinumab, is administered byintravenous, cutaneous or subcutaneous injection, the IL-17 antibodywill be in the form of a pyrogen-free, parenterally acceptable solution.A pharmaceutical composition for intravenous, cutaneous, or subcutaneousinjection may contain, in addition to the IL-17 antibody or antigenbinding fragments thereof, e.g., secukinumab, an isotonic vehicle suchas sodium chloride, Ringer's, dextrose, dextrose and sodium chloride,lactated Ringer's, or other vehicle as known in the art.

The appropriate dosage will, of course, vary depending upon, forexample, the particular IL-17 antibodies or antigen binding fragmentsthereof, e.g., secukinumab, to be employed, the host, the mode ofadministration and the nature and severity of the condition beingtreated, and on the nature of prior treatments that the patient hasundergone. Ultimately, the attending health care provider will decidethe amount of the IL-17 antibody with which to treat each individualpatient. In some embodiments, the attending health care provider mayadminister low doses of the IL-17 antibody and observe the patient'sresponse. In other embodiments, the initial dose(s) of IL-17 antibodyadministered to a patient are high, and then are titrated downward untilsigns of relapse occur. Larger doses of the IL-17 antibody may beadministered until the optimal therapeutic effect is obtained for thepatient, and the dosage is not generally increased further.

An IL-17 antibodies or antigen binding fragments thereof, e.g.,secukinumab, is conveniently administered parenterally, intravenously,e.g., into the antecubital or other peripheral vein, intramuscularly, orsubcutaneously. The duration of therapy using a pharmaceuticalcomposition of the present disclosure will vary, depending on theseverity of the disease being treated and the condition and personalresponse of each individual patient. The health care provider willdecide on the appropriate duration of i.v. or s.c. therapy and thetiming of administration of the therapy, using the pharmaceuticalcomposition of the present disclosure.

The timing of dosing is generally measured from the day of the firstdose of the active compound (e.g., secukinumab), which is also known as“baseline”. However, different health care providers use differentnaming conventions, as shown in Table 5, below.

TABLE 5 Common naming conventions for dosing regimens. Bolded itemsrefer to the naming convention used herein. Week 0/1 1/2 2/3 3/4 4/5 5/66/7 7/8 8/9 Etc. 1st 0/1 7/8 14/15 21/22 28/29 35/36 42/43 49/50 56/57Etc. day

Notably, week zero may be referred to as week 1 by some health careproviders, while day zero may be referred to as day one by some healthcare providers. Thus, it is possible that different physicians willdesignate, e.g., a dose as being given during week 3/on day 21, duringweek 3/on day 22, during week 4/on day 21, during week 4/on day 22,while referring to the same dosing schedule. For consistency, the firstweek of dosing will be referred to herein as week 0, while the first dayof dosing will be referred to as day 1. However, it will be understoodby a skilled artisan that this naming convention is simply used forconsistency and should not be construed as limiting, i.e., weekly dosingis the provision of a weekly dose of the IL-17 antibodies or antigenbinding fragments thereof, e.g., secukinumab, regardless of whether thephysician refers to a particular week as “week 1” or “week 2”. As anexample of naming using the convention designated herein, five doses ofsecukinumab administered weekly may be provided during week 0 (e.g., onabout day 1), during week 1 (e.g., on about day 8), during week 2 (e.g.,on about day 15), during week 3 (e.g., on about day 22), and during week4 (e.g., on about day 29). It will be understood that a dose need not beprovided at an exact time point, e.g., a dose due approximately on day29 could be provided, e.g., on day 24 to day 34, e.g., day 30, as longas it is provided in the appropriate week.

In some embodiments, the disclosed methods and uses employ an initial(sometimes called “induction”) regimen that lasts 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, theinitial regimen is weeks 0, 1, 2, and 3. In other embodiments, theinduction regimen is eight or twelve weeks, preferably twelve weeks. Insome embodiments, the induction regimen employs a loading regimen. Insome embodiments, the loading regimen comprises administering several(e.g., 1, 2, 3, 4, 5, 6, 7, preferably 4 or 5) doses of about 150 mg-300mg, e.g., about four or five doses of 150 mg or 300 mg (preferably fivedoses of about 150 mg-about 300 mg) of the IL-7 antibody, e.g.,secukinumab. In further embodiments, loading doses are delivered weekly,bi-weekly, every other week, or monthly [every 4 weeks], preferablyweekly. In some embodiments, the disclosed methods, kits and uses employ150 mg or 300 mg of the IL-17 antibody, e.g., secukinumab bysubcutaneous injection, with initial dosing at weeks 0, 1, 2 and 3.

In some embodiments, two additional doses (e.g., 150 mg or 300 mg) ofthe IL-17 antibody, e.g., secukinumab, may be provided (e.g., during theinduction regimen), e.g., during week 8 and 12. In other embodiments,three additional doses (e.g., 150 mg or 300 mg) of secukinumab may beprovided (e.g., during the induction regimen), e.g., during week 8, 9and 12; week 8, 10 and 12; or week 8, 11, and 12 (preferably week 8, 9and 12).

It will be understood that in some embodiments, the disclosed methods,uses and kits may require up-titration of the IL-17 antibody (e.g.,secukinumab) (e.g., from 150 mg to 300 mg) and/or addition of a furtherdose the IL-17 antibody (e.g., secukinumab) (e.g., an additional dose atweek nine). For example, following treatment with several doses of theIL-17 antibody (e.g., secukinumab), a clinician may perform anevaluation, e.g., PASI, JDA, CGI (e.g., clinical components of a CGIevaluation) to determine if the patient is responding as desired to thetreatment. This evaluation may be performed at any time during theinduction regimen, e.g., the evaluation may be performed betweenadministration of the dose during week 4 and week 8, or the evaluationmay be performed between administration of the dose during week 8 andweek 12. In preferred embodiments, the evaluation is performed betweenadministration of the dose during week 4 and week 8. As a result of theevaluation, the clinician may, e.g., assign the patient to a treatmentassessment based on the evaluation that is performed. In someembodiments, assignment to a treatment assessment “very much improved”or “much improved” as part of a CGI evaluation provides an indicationthat no up-titration of the IL-17 antibody (e.g., secukinumab) isrequired, and assignment to a treatment assessment “worse”, “no change”or “minimally improved” as part of a CGI evaluation provides anindication that up-titration of the IL-17 antibody (e.g., secukinumab)is required. Following evaluation and assignment to a treatmentassessment, the patient may be administered the same dose, e.g., about150 mg, of the IL-17 antibody (e.g., secukinumab) for the remainder ofthe induction regimen (e.g., during week 8 and 12) if no up-titration isrequired, or the patient may be administered an increased dose, e.g., adouble dose (e.g., about 300 mg), of the IL-17 antibody (e.g.,secukinumab) for the remainder of the induction regimen (e.g., duringweeks 8, 9 and 12). If uptitration occurs during the induction regimen,generally the uptitrated dose will also be used during the maintenanceregimen.

As used herein, “clinical components of a CGI” refers to area oferythema with pustules, area of erythema, areas of edema and fevermeasured as part of a CGI evaluation; it excludes levels of WBC, CRP andserum albumin.

An initial (induction) regimen for delivery of an IL-17 antibodies orantigen binding fragments thereof, e.g., secukinumab, may be designedusing PK information (see Table 6), rather than specific dosages. Forthe disclosed regimens and methods, an artisan may deliver an IL-17antibody or antigen binding fragment thereof, e.g., secukinumab, duringan induction regimen to provide a mean trough level of about 29.2 μg/mL(with a 30-40% inter-patient variation). Alternatively, an artisan maydeliver an IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab, during an induction regimen to provide a C_(max) for atypical 90 kg patient of between about 52 μg/ml-about 104 μg/ml. In someembodiments, the IL-17 antibody, e.g., secukinumab, has a T_(max) ofabout 7-8 days and an elimination half-life of about 30 days.

For a maintenance regimen, a dose may be provided every month (alsocalled “monthly” dosing) (i.e., every 4 weeks, i.e., about every 28days), every two months (i.e., every 8 weeks, i.e., about every 56days), or every three months (i.e., every 12 weeks, i.e., about every 84days). In some embodiments, the maintenance regimen begins followingweek 12. A first dose of a maintenance regimen will be administered on adate usually measured from the final dose of the induction regimen.Thus, as an example, if the final dose of the induction regimen isprovided during week 12, then the first dose as part of a monthly [every4 weeks] maintenance regimen will be delivered during week 16, the firstdose as part of an every two month maintenance regimen will be deliveredduring week 20, the first dose as part of an every three monthmaintenance regimen will be delivered during week 24, etc. In someembodiments, the maintenance regimen comprises administering a dose ofthe IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab, weekly, every two weeks, monthly [every 4 weeks], everyother month, quarterly, bi yearly, or yearly. In some embodiments, themaintenance regimen employs monthly dosing (every 4 weeks). In someembodiments, the first dose of the maintenance regimen is deliveredduring week 4 or during 16. In some embodiments, the maintenance regimencomprises administering a dose of about 150 mg-300 mg, e.g., about 150mg or about 300 mg of the IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab. In some embodiments the patient isadministered a dose of about 150 mg-about 300 mg (e.g., about 150 mg orabout 300 mg) by subcutaneous injection with initial dosing at weeks 0,1, 2 and 3, followed by monthly maintenance dosing, starting at week 4.A 300 mg dose may be given as two subcutaneous injections of 150 mg.

It will be understood that in some embodiments, a maintenance regimenmay require up-titration (e.g., from 150 mg to 300 mg) and/or additionof further doses. For example, any time during the maintenance regimen,a clinician may perform an evaluation, e.g., PASI, JDA, CGI (e.g.,clinical components of a CGI evaluation) to determine if the patient isresponding as desired to the treatment. The clinician may thereafterassign the patient to a treatment assessment based on the evaluationthat is performed. In some embodiments, assignment to a treatmentassessment “very much improved” or “much improved” as part of a CGIevaluation provides an indication that no up-titration of the IL-17antibody (e.g., secukinumab) is required, and assignment to a treatmentassessment “worse”, “no change” or “minimally improved” as part of a CGIevaluation provides an indication that up-titration of the IL-17antibody (e.g., secukinumab) is required. Following evaluation andassignment to a treatment assessment, the patient may be administeredthe same dose, e.g., about 150 mg, of the IL-17 antibody (e.g.,secukinumab) for the remainder of the maintenance regimen if noup-titration is required, or the patient may be administered anincreased dose, e.g., about 300 mg, of the IL-17 antibody (e.g.,secukinumab) for the remainder of the maintenance regimen. Ifuptitration occurs during the maintenance regimen, generally the patientwill remain on the uptitrated dose during the maintenance regimen.

A maintenance regimen for delivery of an IL-17 antibody, such assecukinumab, may also be designed using PK information (see Table 6),rather than specific dosages. For the disclosed regimens and methods, anartisan may deliver an IL-17 antibody, such as secukinumab, during amaintenance regimen to provide an average steady-state trough level ofabout 15 μg/mL (with a 30-40% inter-patient variation). Alternatively,an artisan may deliver an IL-17 antibody, e.g., secukinumab, during aninduction regimen to provide an average steady-state trough level for atypical 90 kg patient of between about 5 μg/ml-about 70 μg/ml, e.g.,about 5 μg/ml-about 33 μg/ml or about 11 μg/ml-about 70 μg/ml,preferably about 16 μg/ml or about 33 μg/ml. In some embodiments, theIL-17 antibody, e.g., secukinumab, has a T_(max) of about 7-8 days. Insome embodiments, the IL-17 antibody, e.g., secukinumab, has anelimination half-life of about 30 days.

Delivery of an IL-17 antibody, such as secukinumab, during a loadingregimen, induction regimen and/or maintenance regimen may be via asubcutaneous route, e.g., delivery of dosages of about 75 mg-about 300mg (e.g., about 50 mg, about 75 mg, about 100 mg, about 125 mg, about150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mag, about275 mg, about 300 mg, about 325 mg), via an intravenous route, e.g.,delivery of dosages of about 1 mg/kg-about 50 mg/kg (e.g., about 1mg/kg, about 3 mg/kg, about 10 mg/kg, about 30 mg/kg, about 40 mg/kg,about 50 mg/kg, etc.) or any other route of administration (e.g,intramuscular, i.m.). In preferred embodiments, the dose of the IL-17antibody is delivered s.c.

Disclosed herein are methods of treating Generalized Pustular Psoriasis(GPP), comprising administering to a patient in need thereof an IL-17antibody or antigen binding fragment thereof, wherein the IL-17 antibodyor antigen binding fragment binds to an epitope of an IL-17 homodimerhaving two mature human IL-17 protein chains, said epitope comprisingLeu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127,Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on theother chain, wherein the IL-17 antibody or antigen binding fragmentthereof has a K_(D) of about 100-about 200 pM (e.g., as measured byBiacore®), and wherein the IL-17 antibody or antigen binding fragmentthereof has an in vivo half-life of about 23-about 30 days.

Disclosed herein are methods of treating GPP, comprising subcutaneouslyadministering an IL-17 antibody or antigen binding fragment thereof to apatient in need thereof as a dose of about 150 mg-about 300 mg withinitial dosing at weeks 0, 1, 2 and 3, followed by monthly dosingstarting at week 4.

Disclosed herein are methods of treating GPP, comprising: a)subcutaneously administering an IL-17 antibody or antigen bindingfragment thereof to a patient in need thereof at a dose of about 150 mgduring weeks 0, 1, 2, 3, and 4; and b) thereafter, subcutaneouslyadministering the IL-17 antibody or antigen binding fragment thereof tothe patient at a dose of about 300 mg during week 8, 9, and 12 and thenmonthly thereafter, beginning during week 16.

Disclosed herein are methods of treating GPP, comprising: a)subcutaneously administering an IL-17 antibody or antigen bindingfragment thereof to a patient in need thereof at a dose of about 150 mgduring weeks 0, 1, 2, 3, and 4; b) assigning the patient to a treatmentassessment based on clinical components of a CGI evaluation administeredduring week 8, wherein assigning a treatment assessment “very muchimproved” or “much improved” provides an indication that no up-titrationis required, and wherein assigning a treatment assessment “worse”, “nochange” or “minimally improved” provides an indication that up-titrationis required; and c) i) thereafter, subcutaneously administering theIL-17 antibody or antigen binding fragment thereof to the patient at adose of about 150 mg monthly, beginning during week 8, if noup-titration is required; or ii) thereafter, subcutaneouslyadministering the IL-17 antibody or antigen binding fragment thereof tothe patient at a dose of about 300 mg during weeks 8, 9 and 12 and thenmonthly thereafter, beginning during week 16, if up-titration isrequired.

Disclosed herein are IL-17 antibodies or antigen binding fragmentsthereof for use in treating Generalized Pustular Psoriasis (GPP) in apatient in need thereof, characterized in that the IL-17 antibody orantigen binding fragment thereof binds to an epitope of an IL-17homodimer having two mature human IL-17 protein chains, said epitopecomprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126,Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79,Asp80 on the other chain, wherein the IL-17 antibody or antigen bindingfragment thereof has a K_(D) of about 100-about 200 pM (e.g., asmeasured by Biacore®), and wherein the IL-17 antibody or antigen bindingfragment thereof has an in vivo half-life of about 23-about 30 days

Disclosed herein are IL-17 antibodies or antigen binding fragmentsthereof for use in treating GPP in a patient in need thereof,characterized in that the IL-17 antibody or antigen binding fragmentthereof is to be subcutaneously administered to the patient as a dose ofabout 150 mg-about 300 mg with initial dosing at weeks 0, 1, 2 and 3,followed by monthly dosing starting at week 4.

Disclosed herein are IL-17 antibodies or antigen binding fragmentsthereof for use in treating GPP in a patient in need thereof,characterized in that the IL-17 antibody or antigen binding fragmentthereof is to be administered to the patient: a) subcutaneously at adose of about 150 mg during weeks 0, 1, 2, 3, and 4; and b) thereafter,subcutaneously at a dose of about 300 mg during week 8, 9, and 12 andthen monthly thereafter, beginning during week 16.

Disclosed herein are IL-17 antibodies or antigen binding fragmentsthereof for use in treating GPP in a patient in need thereof,characterized in that the IL-17 antibody or antigen binding fragmentthereof is to be administered to the patient: a) subcutaneously at adose of about 150 mg during weeks 0, 1, 2, 3, and 4; b) i) thereafter,subcutaneously at a dose of about 150 mg monthly, beginning during week8, if no up-titration is required; or ii) thereafter, subcutaneously ata dose of about 300 mg during weeks 8, 9 and 12 and then monthlythereafter, beginning during week 16, if up-titration is required,wherein prior to step b), the patient is assigned to a treatmentassessment based on clinical components of a CGI evaluation administeredduring week 8, wherein assigning a treatment assessment “very muchimproved” or “much improved” provides an indication that no up-titrationis required, and wherein assigning a treatment assessment “worse”, “nochange” or “minimally improved” provides an indication that up-titrationis required. In some embodiments of the disclosed methods or uses, thepatient has von Zumbusch GPP, generalized form of acrodermatitiscontinua (Hallopeau), acute exanthematic, GPP of pregnancy (impetigoherpetiformis), infantile or juvenile GPP, or circinate or annular GPP.

In some embodiments of the disclosed methods or uses, the clinicalcomponents of the CGI are area of erythema with pustules, area oferythema, area of edema and fever.

In some embodiments of the disclosed methods or uses, the patient has areduction in GPP as assessed by measuring levels of IL-10 and/or IL-22in response to treatment with the IL-17 antibody.

In some embodiments of the disclosed methods or uses, the patient has areduction in disease as assessed by the Japanese DermatologicalAssociation (JDA) severity index for GPP, Clinical Global Impression(CGI) assessment, and/or Psoriasis Area and Severity Index (PAST) inresponse to treatment with the IL-17 antibody.

In some embodiments of the disclosed methods or uses, the patient haserythema with pustules ≥10% prior to treatment with the IL-17 antibodyor antigen binding framente thereof (e.g., secukinumab). In someembodiments of the disclosed methods or uses, the patient has a BodySurface area Affected (BSA) of at least 5% or greater prior to treatmentwith the IL-17 antibody or antigen binding framente thereof (e.g.,secukinumab). In some embodiments of the disclosed methods or uses, thepatient has a Body Surface area Affected (BSA) of at least 10% orgreater prior to treatment with the IL-17 antibody or antigen bindingframente thereof (e.g., secukinumab).

In some embodiments of the disclosed methods or uses, the patient isable to stop or reduce concomitant use of a psoriasis agent by at leastabout 50% in response to treatment with the IL-17 antibody or antigenbinding framente thereof (e.g., secukinumab). In some embodiments, thedisclosed methods or uses, further comprise administering the patient atleast one additional psoriasis agent. In some embodiments of thedisclosed methods or uses, the additional psoriasis agent is selectedfrom the group consisting of ustekinumab, a TNF alpha antagonist (suchas etanercept, adalimumab, infliximab), a systemic corticosteroid,cyclosporin, etretinate, and methotrexate.

In some embodiments of the disclosed methods or uses, the patient hasGPP without psoriasis vulgaris (PV). In some embodiments of thedisclosed methods or uses, the patient has GPP with psoriasis vulgaris(PV). In some embodiments, the patient has a decreased level ofInterleukin-36 Receptor Antagonist (e.g., mRNA or protein) in the skinrelative to a subject not having GPP. In some embodiments, the patientis selected for treatment with the IL-17 antibody or antigen bindingfragment thereof based on having been previously determined to have adecreased level of Interleukin-36 Receptor Antagonist (mRNA or protein)in the skin relative to a subject not having GPP.

As used herein, the phrase “container having a sufficient amount of theIL-17 antibody to allow delivery of [a designated dose]” is used to meanthat a given container (e.g., vial, pen, syringe) has disposed therein avolume of an IL-17 antibody (e.g., as part of a pharmaceuticalcomposition) that can be used to provide a desired dose. As an example,if a desired dose is 500 mg, then a clinician may use 2 ml from acontainer that contains an IL-17 antibody formulation with aconcentration of 250 mg/ml, 1 ml from a container that contains an IL-17antibody formulation with a concentration of 500 mg/ml, 0.5 ml from acontainer contains an IL-17 antibody formulation with a concentration of1000 mg/ml, etc. In each such case, these containers have a sufficientamount of the IL-17 antibody to allow delivery of the desired 500 mgdose.

As used herein, the phrase “formulated at a dosage to allow [route ofadministration] delivery of [a designated dose]” is used to mean that agiven pharmaceutical composition can be used to provide a desired doseof an IL-17 antibody, e.g., secukinumab, via a designated route ofadministration (e.g., s.c. or i.v.). As an example, if a desiredsubcutaneous dose is 500 mg, then a clinician may use 2 ml of an IL-17antibody formulation having a concentration of 250 mg/ml, 1 ml of anIL-17 antibody formulation having a concentration of 500 mg/ml, 0.5 mlof an IL-17 antibody formulation having a concentration of 1000 mg/ml,etc. In each such case, these IL-17 antibody formulations are at aconcentration high enough to allow subcutaneous delivery of the IL-17antibody. Subcutaneous delivery typically requires delivery of volumesof less than about 2 ml, preferably a volume of about 1 ml or less.However, higher volumes may be delivered over time using, e.g, apatch/pump mechanism.

Disclosed herein is the use of an IL-17 antibody (e.g., secukinumab) forthe manufacture of a medicament for the treatment of GPP in a patient,wherein the medicament is formulated to comprise containers, eachcontainer having a sufficient amount of the IL-17 antibody to allowdelivery of at least about 75 mg, 150 mg or 300 mg IL-17 antibody orantigen binding framente thereof (e.g., secukinumab) per unit dose.

Disclosed herein is the use of an IL-17 antibody (e.g., secukinumab) forthe manufacture of a medicament for the treatment of GPP in a patient,wherein the medicament is formulated at a dosage to allow systemicdelivery (e.g., i.v. or s.c. delivery) 75 mg, 150 mg or 300 mg IL-17antibody or antigen binding framente thereof (e.g., secukinumab) perunit dose.

Treat to Target (Plaque-Type Psoriasis)

This disclosure also contemplates improved treatment regimens forplaque-type psoriasis. Up-titration, optionally along with delivery ofadditional doses (e.g., 1 or 2 additional doses), can be employed toenhance treatment response in plaque-type psoriasis. According toInternational Patent Publication WO2012/045848, a plaque-type psoriasispatient is typically administered about 150 mg-about 300 mg secukinumabas part of an induction regimen at weeks 0, 1, 2, 3, 4, 5, 8, and 12 andthereafter the patient is typically administered about 150 mg-about 300mg secukinumab as part of a monthly (i.e., every 4 weeks) maintenanceregimen (i.e., on the whole, secukinumab is delivered weekly for fourweeks, and every four weeks thereafter (starting at week 4)). Animproved treatment regimen for plaque-type psoriasis includes treatmentof the patient with about 150 mg secukinumab during week 0, 1, 2, 3, 4,and 8. However, prior to treatment at week 12, the patients's PASI scoremay be assessed and those patients not having achieved, e.g., PASI 75 orPASI 90 (preferably not having achieved PASI 90) at week 12 may beup-titrated to, e.g., a double dose (e.g., about 300 mg) of the IL-17antibody (e.g., secukinumab) for a week 12 dose and, optionally, may begiven an additional dose (e.g., a double dose (e.g., about 300 mg))during week 13. These patients will be treated with the increased dose(e.g., the double dose (e.g., about 300 mg)) of the IL-17 antibody(e.g., secukinumab) during week 16 and monthly (i.e., every 4 weeks)thereafter. PASI 90 refers to ≥90% improvement (reduction) in PASI scorecompared to baseline.

Disclosed herein are methods of treating plaque-type psoriasis,comprising: a) administering an IL-17 antibody (e.g., secukinumab) to apatient in need thereof as weekly doses of about 150 mg during week 0,1, 2, 3, 4, and 8; b) thereafter, determining whether the patient hasachieved PASI 75 or PASI 90 (preferably PASI 90) before week 12; c)administering the patient about 300 mg of the IL-17 antibody during week12 and, optionally seek 13, if the patient has not achieved PASI 75 orPASI 90 (preferably PASI 90) according to step b); and d) thereafteradministering the IL-17 antibody to the patient monthly (i.e., every 4week) at a dose of about 300 mg, beginning during week 16.

Another improved treatment regimen employing up-titration forplaque-type psoriasis includes treatment of the patient with about 150mg secukinumab during week 0, 1, 2, 3, 4, 8 and 12. However, prior totreatment at week 16, the patients's PASI score may be assessed andthose patients not having achieved, e.g., PASI 75 or PASI 90 (preferablynot having achieved PASI 90) before week 16 may be up-titrated to, e.g.,a double dose (e.g., about 300 mg) of the IL-17 antibody (e.g.,secukinumab) for a week 16 dose. These patients will be treated with theincreased dose (e.g., the double dose (e.g., about 300 mg)) of the IL-17antibody (e.g., secukinumab) during Week 16 and monthly (i.e., every 4weeks) thereafter.

Disclosed herein are methods of treating plaque-type psoriasis,comprising: a) administering an IL-17 antibody (e.g., secukinumab) to apatient in need thereof as weekly doses of about 150 mg during week 0,1, 2, 3, 4, 8, and 12; b) thereafter, determining whether the patienthas achieved PASI 75 or PASI 90 (preferably PASI 90) before week 16; andc) thereafter, administering the IL-17 antibody to the patient monthly(i.e., every 4 week) at a dose of about 300 mg, beginning during week16, if the patient has not achieved PASI 75 or PASI 90 (preferably PASI90) according to step b).

Another improved treatment regimen for plaque-type psoriasis includesdown-titration of the amount of secukinumab given to the patient. Inthis manner, less antibody drug may be delivered to the patient, whichis regarded as a safety benefit. For example, an improved treatmentregimen for plaque-type psoriasis includes treatment of the patient withabout 300 mg secukinumab during week 0, 1, 2, 3, 4, 8, and 12. However,prior to treatment at week 16, the patients's PASI score may be assessedand those patients having achieved, e.g., PASI 75 or PASI 90 (preferablyhaving achieved PASI 90) before week 16 may be down-titrated to, e.g.,about 150 mg of the IL-17 antibody (e.g., secukinumab), for a week 16dose. These patients will be treated with this decreased dose (e.g.,about 150 mg) of the IL-17 antibody (e.g., secukinumab) during week 16and monthly (i.e., every 4 weeks) thereafter.

Disclosed herein are methods of treating plaque-type psoriasis,comprising: a) administering an IL-17 antibody (e.g., secukinumab) to apatient in need thereof as weekly doses of about 300 mg during week 0,1, 2, 3, 4, 8, and 12; and b) thereafter, administering the IL-17antibody to the patient monthly (i.e., every 4 week) at a dose of about150 mg, beginning during Week 16.

Disclosed herein are methods of treating plaque-type psoriasis,comprising: a) administering an IL-17 antibody (e.g., secukinumab) to apatient in need thereof as weekly doses of about 300 mg during week 0,1, 2, 3, 4, 8, and 12; b) thereafter, determining whether the patienthas achieved PASI 75 or PASI 90 (preferably PASI 90) before week 16; andc) thereafter, administering the IL-17 antibody to the patient monthly(i.e., every 4 week) at a dose of about 150 mg, beginning during week16, if the patient has achieved PASI 75 or PASI 90 (preferably PASI 90)according to step b).

Alternatively, improved treatment regimen for plaque-type psoriasisincludes modification of the treatment timing (increased or decreasedfrequency of drug administration), rather than modification of thedosage (up-titration or down-titration of drug). Fore example, in oneembodiment the patient is treated with about 150 mg or 300 mg(preferably about 150 mg) secukinumab during week 0, 1, 2, 3, 4, 8, and12. However, prior to treatment (e.g., at week 16), the patients's PASIscore may be assessed and if the patient has achieved clear or almostclear skin (e.g., PASI 90), the patient may thereafter be dosed lessfrequently during the maintenance regimen, e.g., every 6 weeks (ratherthan monthly [every 4 weeks]). If clearance (e.g., PASI90) is laterlost, then these patients may resume treatment during the maintenanceregimen on a monthly basis [every 4 weeks]. Conversely, those patientsnot having achieved clearance (e.g., PASI90) (e.g., before week 16) maybe dosed more frequently during the maintenance regimen, e.g., every 2weeks (rather than monthly [every 4 weeks]). If PASI90 is laterachieved, then these patients may resume treatment during themaintenance regimen on a monthly basis [every 4 weeks]. Testing forPASI90 response with the goal to modify treatment timing may take placebefore treatment at week 8, 12, 16, 20, 24, etc. (preferably before week16, most preferably between week 12 and 16).

Disclosed herein are methods of treating plaque-type psoriasis,comprising: a) administering an IL-17 antibody (e.g., secukinumab) to apatient in need thereof as weekly doses of about 150 mg to about 300 mgduring week 0, 1, 2, 3, 4, 8, 12, 16, and 20; and b) thereafter,administering the patient about 150 mg to about 300 mg of the IL-17antibody every 6 weeks, beginning during week 24.

Disclosed herein are methods of treating plaque-type psoriasis,comprising: a) administering an IL-17 antibody (e.g., secukinumab) to apatient in need thereof as weekly doses of about 150 mg to about 300 mgduring week 0, 1, 2, 3, 4, 8, 12, 16, and 20; b) thereafter, determiningwhether the patient has achieved PASI 75 or PASI 90 (preferably PASI 90)by week 24; c) thereafter, administering the patient about 150 mg toabout 300 mg of the IL-17 antibody every 6 weeks, beginning during week24, if the patient has achieved PASI 75 or PASI 90 (preferably PASI 90)by week 24 according to step b).

Disclosed herein are methods of treating plaque-type psoriasis,comprising: a) administering an IL-17 antibody (e.g., secukinumab) to apatient in need thereof as weekly doses of about 150 mg to about 300 mg(e.g., about 150 mg or about 300 mg) during week 0, 1, 2, 3, 4, 8, and12; and b) thereafter, administering the patient about 150 mg to about300 mg (e.g., about 150 mg or about 300 mg) of the IL-17 antibody every6 weeks, beginning during week 16.

Disclosed herein are methods of treating plaque-type psoriasis,comprising: a) administering an IL-17 antibody (e.g., secukinumab) to apatient in need thereof as weekly doses of about 150 mg to about 300 mgduring week 0, 1, 2, 3, 4, 8, and 12; b) thereafter, determining whetherthe patient has achieved PASI 75 or PASI 90 (preferably PASI 90) by week16; c) thereafter, administering the patient about 150 mg to about 300mg of the IL-17 antibody every 6 weeks, beginning during week 16, if thepatient has achieved PASI 75 or PASI 90 (preferably PASI 90) by week 16according to step b).

Disclosed herein are methods of treating plaque-type psoriasis,comprising: a) administering an IL-17 antibody (e.g., secukinumab) to apatient in need thereof as weekly doses of about 150 mg to about 300 mgduring week 0, 1, 2, 3, 4, 8, 12, 16, and 20; b) thereafter, determiningwhether the patient has achieved PASI 75 or PASI 90 (preferably PASI 90)by Week 24; c) thereafter, administering the patient about 150 mg toabout 300 mg of the IL-17 antibody every 2 weeks, beginning during week24, if the patient has not achieved PASI 75 or PASI 90 (preferably PASI90) by week 24 according to step b).

Disclosed herein are methods of treating plaque-type psoriasis,comprising: a) administering an IL-17 antibody (e.g., secukinumab) to apatient in need thereof as weekly doses of about 150 mg to about 300 mgduring week 0, 1, 2, 3, 4, 8, and 12; b) thereafter, determining whetherthe patient has achieved PASI 75 or PASI 90 (preferably PASI 90) by week16; c) thereafter, administering the patient about 150 mg to about 300mg of the IL-17 antibody every 2 weeks, beginning during week 16, if thepatient has not achieved PASI 75 or PASI 90 (preferably PASI 90) by week16 according to step b).

In some embodiments of the above methods, a physician may wish to employless frequent maintenance dosing if the patient has maintained PASI90for a given time (e.g., the patient displays PASI90 at week 8 through 12[or at both week 8 and 12], at week 16 through week 24 [or at both week16 and week 24]) or the patient has achieved PASI90 by a given timepoint (e.g., the patient displays PASI90 by week 8, by week 12, by week16, etc.). In some embodiments of the above methods, the patient has notpreviously been treated with a biological molecule (e.g., a TNF alfainhibitor, e.g., Enbrel®) for plaque-type psoriasis. In some embodimentsof the above methods, the patient has achieved clear or almost clearskin (e.g., PASI 90) before q6w treatment begins. In some embodiments ofthe above methods, the patient has achieved clear or almost clear skin(e.g., PASI 90) before down-titration from 300 mg to 150 mg begins. Insome embodiments of the above methods, the patient has moderate tosevere plaque psoriasis. In some embodiments of the above methods, thepatient has failed to respond to, or has a contraindication to, or isintolerant to phototherapy or systematic therapy, including ciclosporinor methotrexate (MTX).

Palmoplantar Pustular Psoriasis (PPP)

This disclosure also contemplates treatment regimens for pustularpsoriasis that is confined to the palms and soles of a patient(palmoplantar pustular psoriasis, PPP). Around 20% of patients with PPPmay develop plaque psoriasis symptoms elsewhere on their body. Mostpatients suffering from GPP will also present pustular symptoms on thepalms and soles. Prevalence and incidence worldwide is low (e.g.,1.76/million in France), with the highest prevalence in Japan(7.46/million) (Augey (2006) Eur J Dermatol 16(6): 669-673). Theprevalence of PPP is difficult to estimate, but some publicationsmention a prevalence of 0.01% in the general population (de Waal (2011)J Dermatolog Treat 22(2): 102-105).

High levels of IL-17A are found in tissue and fluids of patientssuffering from PPP, and there is an up-regulation of IL-17 dependentgenes in PPP (Yilmaz, supra; Bissonnette (2013) Journal of the AmericanAcademy of Dermatology 71st Annual Meeting of the American Academy ofDermatology, Miami Beach, Fla., US; Mar. 1-Mar. 5, 2013; ConferencePublication: (var. pagings). 68 (4 SUPPL. 1) (pp. AB201). PPP ischaracterized by sterile pustules on the palms and soles, which eruptrepeatedly over the months or years. The surrounding skin has a scalyand erythematous aspect with cracks that are often painful (Pettey(2003) Am Acad Dermatol 49(2): 271-275; de Waal, supra). The eruptionsinvolve both hands and feet usually, sometimes limited to only hands oronly feet. The skin lesions of palmoplantar pustular psoriasis exist formany years and are very resistant to treatment. Sometimes they disappearon their own, only to reappear again.

A variety of PPP treatments have been tried, including UV-therapy, butmore severe cases or treatment resistant cases may require systemictreatment with methotrexate, cyclosporine, acitretin alone or incombination with cyclosporine, and biological agents. Acitrecin is theonly product which has been approved in Europe for use in PPP. Amongbiological agents, the IL-12/23 inhibitor ustekinumab has been tried,but results are ambiguous. In a case series of four patients, two failedto improve (Gerdes (2010) Br J Dermatol 163(5): 1116-1118). Some authors(Bissonnett, supra) were not able to show clinical benefit with licenseddoses of ustekinumab, while others recently presented a series of 5 casereports successfully treated with ustekinumab (Morales-Munera (2013) BrJ Dermatol 168(4): 820-824). A small placebo-controlled pilot study(n=15) with etanercept 50 mg twice weekly showed a statisticallysignificant difference in ppPASI response at 24 weeks. At 12 weeksetanercept was numerically, but not statistically significantly betterthan placebo (Bissonnette, supra). Alefacept has been reported to bemoderately effective in palmoplantar pustular psoriasis with reductionsin palmoplantar pustulosis PASI (ppPASI) of 49.6% after 16 weeks oftreatment (Guenther (2007) J Cutan Med Surg 11(6): 202-205). As a resultof the difficulty in treating PPP and the ambiguous responses tocurrently available drugs, new treatments for PPP are needed.

IL-17 antibodies, such as secukinumab, are expected to find use in thetreatment of PPP. A PPP patient is typically administered about 150mg-about 300 mg of the IL-17 antibody (e.g., secukinumab) during weeks0, 1, 2, and 3, and then monthly thereafter, beginning during week 4(i.e., on the whole, secukinumab is delivered during week 0, 1, 2, 3, 4,8, 12, 16, 20, 24, etc.). Clinical trial Protocol AIN457A3301, which isincorporated by reference herein, describes the protocol for thistreatment regimen of PPP in detail. The study population comprises arepresentative group of male and female out-patients (18 years old) withmoderate to severe palmoplantar pustular psoriasis (ppPASI≥12 andDLQI≥10) that is poorly controlled by topical treatments and/orultraviolet (UV) light and/or previous systemic therapy, and who arecandidates for biological therapy.

Response to treatment for PPP patients may be measured by ppPASI. TheppPASI is a modification of the PASI score and adjusted for palmoplantarpustular psoriasis whereby the classification of thickening of the skinhas been replaced by classification and scoring of vesicles/pustules(Fredriksson (1978) Dermatologica 157(4): 238-244). The maximum totalscore on the ppPASI system is 72. Other response indicies include: thePASI scoring system, Investigator's Global Assessment mod 2011 (IGA mod2011), Dermatology Life Quality Index (DLQI) and Subject's GlobalAssessment (SGA), Work Productivity and Activity ImpairmentQuestionnaire-Psoriasis (WPAI-PSO), Palmar-Pustular Quality of LifeIndex (ppQoL-Index).

Disclosed herein are methods of treating palmoplantar pustularpsoriasis, PPP, comprising: subcutaneously administering an IL-17antibody (e.g., secukinumab) to a patient in need thereof as a dose ofabout 150 mg to about 300 mg with initial dosing at weeks 0, 1, 2 and 3,followed by monthly maintenance dosing starting at week 4. In someembodiments, the patient has PPP accompanying chronic plaque-typepsoriasis. In some embodiments, the patient has PPP accompanying GPP.

Combination Therapies

In practicing some of the methods of treatment or uses of the presentdisclosure, a therapeutically effective amount of an IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab, is administered toa patient, e.g., a mammal (e.g., a human). While it is understood thatthe disclosed methods provide for treatment of patients with an IL-17antibody, this does not imply that the IL-17 antibody-based therapy isnecessarily a monotherapy. Indeed, if a patient is selected fortreatment with an IL-17 antibody, then the IL-17 antibody (e.g.,secukinumab) may be administered in accordance with the method of thedisclosure either alone or in combination with other therapeutics fortreating GPP, plaque-type psoriasis and/or PPP (as the case may be)disease in patients, e.g., in combination with cyclosporin. Whencoadministered with one or more additional therapeutics, an IL-17antibody may be administered either simultaneously with the othertherapeutic, or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering the IL-17 antibody in combination with other therapeutics,as well as the appropriate dosages for co-delivery.

Various therapies may be beneficially combined with the disclosed IL-17antibodies, such as secukinumab, during treatment of PV, GPP and/or PPP.Such therapies include topicals (over the counter, non-steroidalcompounds and steroidal compound), phototherapy and systemic treatment(e.g., with biologis or chemical entities).

Non-limiting examples of topical psoriasis agents for use with thedisclosed IL-17 antibodies, such as secukinumab, include salicylic acid,coal tar, Dovonex® (calcipotriene), Taclonex® (calcipotriene andbetamethasone dipropionate), Tazorec® (tazarotene), pimecrolimus,tacrolimus, Vectical® (calcitriol), Zithranol-RR® (anthralin) andtopical steroids (e.g., corticosteroids).

Examples of phototherapy for use with the disclosed IL-17 antibodies,such as secukinumab, include treatment with psoralen+UVA (PUVA) ortreatment with UVB (with or without tar).

Examples of psoriasis agents used in systemic treatment for use with thedisclosed IL-17 antibodies, such as secukinumab, include retionoids suchas Acitretin (e.g., Soriatane®), cyclosporine, methotrexate, hydroxyurea(e.g., Hydrea®), isotretinoin, mycophenolate mofetil, mycophenolic acid,sulfasalazine, 6-thioguanine, fumarates (e.g, dimethylfumarate andfumaric acid esters), azathioprine, corticosteroids, leflunomide,tacrolimus, T-cell blockers (such as Amevive® (alefacept) and Raptiva®(efalizumab), tumor necrosis factor-alpha (TNF-alpha) blockers (such asEnbrel® (etanercept), Humira® (adalimumab), Remicade® (infliximab) andSimponi® (golimumab)) and interleukin 12/23 blockers (such as Stelara®(ustekinumab), tasocitinib, and briakinumab.

Additional psoriasis agents for use in combination with the disclosedIL-17 antibodies, such as secukinumab, during treatment of psoriasisinclude apremilast, mometasome, voclosporin, ketokonazol, NeuroskinForte, recombinant human interleukin-10, voclosporin, MK-3222,tofacitinib, VX-765, MED-I545, fluphenazine decanoate, acetomuinophn,bimosiamose cream, doxycycline, vancomycin, AbGn168, Vitamin D3,R05310074, fludarabine Calcipotriol and hydrocortisone (LEO 80190),LE80185 (Taclonex® Scalp topical suspension/Xamiol® gel), Focetria(Monovalent MF59-Adjuvanted vaccine, tgAAC94 gene therapy vector,Apremilast, Capsaicin, Psirelax, ABT-874 (anti IL-12), IDEC-114,MEDI-522, INCB018424 phosphate cream, LE29102, BMS 587101, CD 2027,CRx-191, 8-methoxypsoralen or 5-methoxypsoralen, Bicillin L-A,LY2525623, INCB018424, LY2439821, CEP-701, CC-10004, certolizumab (CZP),GW786034 (pazopanib), doxycycline Curcuminoids C3 Complex, NYC 0462,RG3421, hOKT3gammal(Ala-Ala), BT061, teplizumab, Chondroitin sulphate,CNTO 1275, monoclonal antibody to IL-12p40 and IL-23 p40 subunits,BMS-582949, MK0873, MEDI-507, M518101, ABT-874, AMG 827, AN2728, AMG714, AMG 139, PTH (1-34), U0267 Foam, CNTO 1275, QRX-101, CNTO 1959, LEO22811, Imiquimod, CTLA4Ig, Alga Dunaliella Bardawil, AS101 Cream,pioglitazone, pimecrolimus, ranibizumab, Zidovudine CDP870 (Certolizumabpegol), Onercept (r-hTBP-1), ACT-128800,4,4-dimethyl-benziso-2H-selenazine, CRx-191, CRx-197, doxercalciferol,LEO 19123 Cream (calcipotriol plus LEO 80122), LAS 41004, WBI-1001,tacrolimus, RAD001, rapamycin, rosiglitazone, pioglitazone, ABT-874,Aminopterin, AN2728, CD2027, ACT-128800, mometasone furoate, CT 327,clobetasol+LCD, BTT1023, E6201, topical vitamin B12, INCB018424Phosphate Cream, Xamiol gel, IP10.C8, BFH772, LEO 22811, Fluphenazine,MM-093, Clobex, SCH 527123, CF101, SRT2104, BIRT2584, CC10004,Tetrathiomolybdate, CP-690,550, U0267, ASP015K, VB-201, Acitretin (alsocalled U0279), RWJ-445380, Psoralait, Clobetasol propionate, botulinumtoxin type A, alefacept, erlotinib, BCT194, Ultravate Ointment,Roflumilast, CNTO 1275, halobetasol, ILV-094, CTA018 cream, COL-121,MEDI-507, AEB071. Additional agents for use in combination withsecukinumab during treatment of psoriasis include IL-6 antagonists, CD20antagonistis, CTLA4 antagnonists, IL-17 antagonists, IL-8 antagnoists,IL-21 antagonistis, IL-22 antagonist, VGEF antagnosits, CXCLantagonists, MMP antagonists, defensin antagonists, IL-1betaantagonists, and IL-23 antagonists (e.g., receptor decoys, antagonisticantibodies, etc.). A skilled artisan will be able to discern theappropriate dosages of the above agents for co-delivery with thedisclosed IL-17 antibodies, such as secukinumab.

In some embodiments of the disclosure, prior to treatment with the IL-17antagonist, e.g., IL-17 antibodies or antigen binding fragments thereof,the patient is undergoing treatment with another psoriasis agent. Insome embodiments of the disclosed methods, uses and kits, the additionalpsoriasis agent is selected from the group consisting of ustekinumab, aTNF alpha antagonist (such as etanercept, adalimumab, infliximab), asystemic corticosteroid, cyclosporin, etretinate, and methotrexate. Insome embodiments of the disclosure, administration of the IL-17 antibody(e.g., secukinumab) allows the patient to completely stop the priorpsoriasis treatment, or, in some embodiments, reduce concomittant use ofthe psoriasis agent by at least about 10%, about 20%, about 25%, about50%, about 75%.

In further embodiments, the patient has not previously been treated forpsoriasis (treatment naïve), has not previously been treatedsystemically for psoriasis (systemic treatment naïve) or has notpreviously been treated for psoriasis using a biological agent(biological naïve).

Kits

The disclosure also encompasses kits for treating a GPP, PPP orplaque-type psoriasis patient (as the case may be) with an IL-17antibody or antigen binding fragment thereof, e.g., secukinumab. Suchkits comprise an IL-17 antibody or antigen binding fragment thereof,e.g., secukinumab (e.g., in liquid or lyophilized form) or apharmaceutical composition comprising the IL-17 antibody (describedsupra). Additionally, such kits may comprise means for administering theIL-17 antibody (e.g., a syringe and vial, a prefilled syringe, aprefilled pen, a patch/pump) and instructions for use. The instructionsmay disclose providing the IL-17 antibody (e.g., secukinumab) to thepatient as part of a specific dosing regimen. These kits may alsocontain additional psoriasis agents (described supra) for treatingpsoriasis, e.g., for delivery in combination with the enclosed IL-17antibody, e.g., secukinumab.

The phrase “means for administering” is used to indicate any availableimplement for systemically administering a drug top a patient,including, but not limited to, a pre-filled syringe, a vial and syringe,an injection pen, an autoinjector, an i.v. drip and bag, a pump,patch/pump, etc. With such items, a patient may self-administer the drug(i.e., administer the drug on their own behalf) or a care-giver or aphysician may administer the drug.

Disclosed herein are kits for the treatment of a patient having GPP,comprising: a) a pharmaceutical composition comprising a therapeuticallyeffective amount of an IL-17 antibody or antigen binding fragmentthereof; b) means for administering the IL-17 antibody or antigenbinding fragment thereof to the patient; and c) instructions providingsubcutaneously administering an IL-17 antibody or antigen bindingfragment thereof to a patient in need thereof as a dose of about 150mg-about 300 mg with initial dosing at weeks 0, 1, 2 and 3, followed bymonthly dosing starting at week 4.

Disclosed herein are kits for the treatment of a patient having GPP,comprising: a) a pharmaceutical composition comprising a therapeuticallyeffective amount of an IL-17 antibody or antigen binding fragmentthereof; b) means for administering the IL-17 antibody or antigenbinding fragment thereof to the patient; and c) instructions providing:i) subcutaneously administering the IL-17 antibody or antigen bindingfragment thereof to the patient at a dose of about 150 mg during weeks0, 1, 2, 3, and 4; ii) I) thereafter, subcutaneously administering theIL-17 antibody or antigen binding fragment thereof to the patient at adose of about 150 mg monthly, beginning during week 8; or II)thereafter, subcutaneously administering the IL-17 antibody or antigenbinding fragment thereof to the patient at a dose of about 300 mg duringweeks 8, 9 and 12 and then monthly thereafter, beginning during week 16.

Disclosed herein are kits for the treatment of a patient having GPP,comprising: a) a pharmaceutical composition comprising a therapeuticallyeffective amount of an IL-17 antibody or antigen binding fragmentthereof; b) means for administering the IL-17 antibody or antigenbinding fragment thereof to the patient; and c) instructions providing:i) subcutaneously administering the IL-17 antibody or antigen bindingfragment thereof to the patient at a dose of about 150 mg during weeks0, 1, 2, 3, and 4; ii) assigning the patient to a treatment assessmentbased on clinical components of a CGI evaluation administered duringweek 8, wherein assigning a treatment assessment “very much improved” or“much improved” provides an indication that no up-titration is required,and wherein assigning a treatment assessment “worse”, “no change” or“minimally improved” provides an indication that up-titration isrequired; and iii) I) thereafter, subcutaneously administering the IL-17antibody or antigen binding fragment thereof to the patient at a dose ofabout 150 mg monthly, beginning during week 8, if no up-titration isrequired; or II) thereafter, subcutaneously administering the IL-17antibody or antigen binding fragment thereof to the patient at a dose ofabout 300 mg during weeks 8, 9 and 12 and then monthly thereafter,beginning during week 16, if up-titration is required.

In some embodiments of the disclosed kits, the patient has von ZumbuschGPP, generalized form of acrodermatitis continua (Hallopeau), acuteexanthematic, GPP of pregnancy (impetigo herpetiformis), infantile orjuvenile GPP, or circinate or annular GPP.

In some embodiments of the disclosed kits, the clinical components ofthe CGI are area of erythema with pustules, area of erythema, area ofedema and fever.

In some embodiments of the disclosed kits, the patient has a reductionin GPP as assessed by measuring levels of IL-10 and/or IL-22 in responseto treatment with the IL-17 antagonist.

In some embodiments of the disclosed kits, the patient has a reductionin disease as assessed by the Japanese Dermatological Association (JDA)severity index for GPP, Clinical Global Impression (CGI) assessment,and/or Psoriasis Area and Severity Index (PAST) in response to treatmentwith the IL-17 antibody.

In some embodiments of the disclosed kits, the patient has erythema withpustules ≥10% prior to treatment with the IL-17 antibody.

In some embodiments of the disclosed kits, the patient has a BodySurface area Affected (BSA) of at least 5% or greater prior to treatmentwith the IL-17 antibody.

In some embodiments of the disclosed kits, the patient has a BodySurface area Affected (BSA) of at least 10% or greater prior totreatment with the IL-17 antibody.

In some embodiments of the disclosed kits, the patient is able to stopor reduce concomitant use of a psoriasis agent by at least about 50% inresponse to treatment with the IL-17 antibody. In some embodiments, thedisclosed kits further comprise instructions directing administering thepatient at least one additional psoriasis agent. In some embodiments ofthe disclosed kits, the additional psoriasis agent is selected from thegroup consisting of ustekinumab, a TNF alpha antagonist (such asetanercept, adalimumab, infliximab), a systemic corticosteroid,cyclosporin, etretinate, and methotrexate.

In some embodiments of the disclosed kits, the patient has GPP withoutpsoriasis vulgaris. In some embodiments of the disclosed kits, thepatient has GPP with psoriasis vulgaris. In some embodiments, thepatient has a decreased level of Interleukin-36 Receptor Antagonist(e.g., mRNA or protein) in the skin relative to a subject not havingGPP. In some embodiments, the patient is selected for treatment with theIL-17 antibody or antigen binding fragment thereof based on having beenpreviously determined to have a decreased level of Interleukin-36Receptor Antagonist (mRNA or protein) in the skin relative to a subjectnot having GPP.

Similar kits are envisioned for plaque-type psoriasis and PPP, said kitshaving appropriate instructions for applying the new dosing regimensplaque-type psoriasis and PPP disclosed herein.

General

In some embodiments, the disclosed methods, treatments, regimens, usesand kits related to GPP, plaque-type psoriasis and PPP employ, insteadof an IL-17 antibody, an IL-17 receptor antibody, e.g., an IL-17receptor antibody having a K_(D) of about 0.29 nm or about 239 pM (e.g.,antibody AM_(H)14/AM_(L)14 of U.S. Pat. No. 7,767,206, brodalumab,AMG-827, the contents of which are incorporated by reference herein inits entirety).

In some embodiments, the disclosed methods, treatments, regimens, usesand kits related to GPP, plaque-type psoriasis and PPP employ an IL-17antibody having a K_(D) of about 1.8 (+/−0.3) pM, binds to an epitope ofan IL-17 protein including Ala79, Asp80, Gly81, Asn82, Val83, Asp84,Tyr85, His86, Met87, Asn88, a mean half-life of about 6.5 days followingintravenous administration of 1 mg/kg, and/or a mean eliminationhalf-life of about 10.3 days following subcutaneous administration of 1mg/kg (e.g., antibody mAb126 of U.S. Pat. No. 7,838,638, Ixekizumab,LY2439821, the contents of which are incorporated by reference herein inits entirety).

In some embodiments of the disclosure, the IL-17 antibody or antigenbinding fragment thereof is selected from the group consisting of: a) anIL-17 antibody that binds to an epitope of IL-17 comprising Leu74,Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128,His129; b) an IL-17 antibody that binds to an epitope of IL-17comprising Tyr43, Tyr44, Arg46, Ala79, Asp80; c) an IL-17 antibody thatbinds to an epitope of an IL-17 homodimer having two mature IL-17protein chains, said epitope comprising Leu74, Tyr85, His86, Met87,Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on one chain andTyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain; d) an IL-17antibody that binds to an epitope of an IL-17 homodimer having twomature IL-17 protein chains, said epitope comprising Leu74, Tyr85,His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 onone chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain,wherein the IL-17 binding molecule has a K_(D) of about 100-about 200 pM(e.g., as measured by Biacore®), and wherein the IL-17 binding moleculehas an in vivo half-life of about 23-about 30 days; and e) an IL-17antibody that comprises an antibody selected from the group consistingof: i) an immunoglobulin heavy chain variable domain (V_(H)) comprisingthe amino acid sequence set forth as SEQ ID NO:8; ii) an immunoglobulinlight chain variable domain (V_(L)) comprising the amino acid sequenceset forth as SEQ ID NO:10; iii) an immunoglobulin V_(H) domaincomprising the amino acid sequence set forth as SEQ ID NO:8 and animmunoglobulin V_(L) domain comprising the amino acid sequence set forthas SEQ ID NO:10; iv) an immunoglobulin V_(H) domain comprising, insequence, the hypervariable regions set forth as SEQ ID NO:1, SEQ IDNO:2, and SEQ ID NO:3; v) an immunoglobulin V_(L) domain comprising, insequence, the hypervariable regions set forth as SEQ ID NO:4, SEQ IDNO:5 and SEQ ID NO:6; vi) an immunoglobulin V_(H) domain comprising, insequence, the hypervariable regions set forth as SEQ ID NO:11, SEQ IDNO:12 and SEQ ID NO:13; vii) an immunoglobulin V_(H) domain comprising,in sequence, the hypervariable regions set forth as SEQ ID NO:1, SEQ IDNO:2, and SEQ ID NO:3 and an immunoglobulin V_(L) domain comprising, insequence, the hypervariable regions set forth as SEQ ID NO:4, SEQ IDNO:5 and SEQ ID NO:6; and viii) an immunoglobulin V_(H) domaincomprising, in sequence, the hypervariable regions set forth as SEQ IDNO:11, SEQ ID NO:12 and SEQ ID NO:13 and an immunoglobulin V_(L) domaincomprising, in sequence, the hypervariable regions set forth as SEQ IDNO:4, SEQ ID NO:5 and SEQ ID NO:6. In some embodiments of thedisclosure, the IL-17 antibody or antigen binding fragment thereof is ahuman antibody. In preferred embodiments of the disclosure, the antibodyis secukinumab.

The details of one or more embodiments of the disclosure are set forthin the accompanying description above. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present disclosure, the preferred methodsand materials are now described. Other features, objects, and advantagesof the disclosure will be apparent from the description and from theclaims. In the specification and the appended claims, the singular formsinclude plural referents unless the context clearly dictates otherwise.Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. All patents and publicationscited in this specification are incorporated by reference. The followingExamples are presented in order to more fully illustrate the preferredembodiments of the disclosure. These examples should in no way beconstrued as limiting the scope of the disclosed patient matter, asdefined by the appended claims.

EXAMPLES

Example 1-Study CAIN457A1302-A multi-center, open label study ofsubcutaneous secukinumab in prefilled syringes as mono- or co-therapy toassess the efficacy, safety and tolerability up to 52 weeks in Japanesesubjects with generalized pustular psoriasis. Purpose and rationale Thepurpose of this study is to assess efficacy and safety data ofsecukinumab in Japanese subjects with generalized pustular psoriasis(GPP). Primary Objective To assess the treatment success of secukinumabin subjects with generalized pustular psoriasis (GPP) at Week 16,relative to baseline (BSL). For the primary objective, treatment successis defined as follows: “Minimally improved”, “Much improved” or “Verymuch improved” in Clinical global impression (CGI) Secondary ObjectivesTo assess the clinically meaningful success of secukinumab in subjectswith generalized pustular psoriasis (GPP) at Week 16, relative tobaseline (BSL). For the secondary objectives, clinically meaningfulsuccess is defined as follows: 1) For subjects who receive secukinumabas monotherapy: “Minimally improved”, “Much improved” or “Very muchimproved” in Clinical global impression (CGI) 2) For subjects whoreceive secukinumab as co-medication together with (an) otherimmunomodulatory drug(s) which is defined as background medication atbaseline: a. ONLY IF the co-medication is not meaningfully reduced:“Minimally improved”, “Much improved” or “Very much improved” in CGI b.ONLY IF the co-medication is meaningfully reduced: “No change”,“Minimally improved”, “Much improved” or “Very much improved” in CGIMeaningful reduction of co-medication is defined as follows; Stop ofco-medication ≥50% reduction of co-medication exposure relative to BSLIf subjects are on secukinumab monotherapy, they have to show clinicalimprovement in order to be considered as subjects with a clinicallymeaningful success. However, there may be subjects entering the trialbecause they do not tolerate their previous treatment any more. Thesesubjects may initially receive secukinumab as co-therapy. The originalmedication would be reduced due to the lack of tolerability. Withoutsecukinumab, this would lead to deterioration of the disease. Hence, forsubjects in this category, staying on the same level of response can beconsidered a clinically meaningful success, IF (and ONLY if) theoriginal medication was meaningfully reduced. To assess the treatmentsuccess and the clinically meaningful success of secukinumab in subjectswith generalized pustular psoriasis (GPP) at Week 52, relative to BSL(The definitions are the same as described above). To assess theefficacy of secukinumab in subjects with GPP with respect to the CGIover time up to Week 52 relative to BSL. To assess the efficacy ofsecukinumab in subjects with GPP with respect to the total score and thecategory of the JDA severity index for GPP over time up to Week 52relative to BSL. To assess the efficacy of secukinumab in subjects withGPP with respect to the score of the following components of the JDAseverity index for GPP over time up to Week 52 relative to BSL: bodysurface area covered with erythema with pustules body surface areacovered with total erythema body surface area covered with edema feverwhite blood cell count C-reactive protein serum albumin To assess theefficacy of secukinumab in subjects with GPP with respect to theobserved value (not scored) of the following components of the JDAseverity index for GPP over time up to Week 52 relative to baseline:Percentage of body surface area covered with erythema with pustulesPercentage of body surface area covered with total erythema Percentageof body surface area covered with edema fever (body temperature, ° C.)white blood cell count (/μL) C-reactive protein (mg/L) serum albumin(g/dL) To assess the clinical safety and tolerability of secukinumab asassessed by vital signs, clinical laboratory variables, ECGs, andadverse events monitoring over time up to Week 60. To describe theefficacy of secukinumab in subjects with GPP with respect to SF-36 overtime up to Week 52 relative to baseline. To describe the efficacy ofsecukinumab in subjects with GPP with respect to changes in DLQI overtime up to Week 52 relative to baseline. To assess the use of systemicco-medication to treat GPP, in subjects who have active GPP treatment atbaseline. To describe the use of topical co-medication to treat GPP, insubjects who have active GPP treatment at baseline. Study design This isa multicenter, single arm, open-label trial in at least 7 (and no morethan 15) subjects with GPP. The study consists of four periods:screening (of up to 4 weeks), induction (of 16 weeks), maintenance (of36 weeks), and post-treatment follow-up period (of 8 weeks). Efficacy,safety and PK trough level measurements of secukinumab will be performedaccording to the visit schedule. All subjects will receive secukinumab150 mg (administered subcutaneously) once weekly for four weeks (at BSL,Weeks 1, 2, 3, and 4). Prior to receiving the Week 8 dose, subjects willbe assigned to the following treatment group based on the clinicalcomponents of their CGI evaluation (area of erythema with pustules, areaof erythema, area of edema, and fever) at Week 8: “No up-titration”: InCGI, “Very much improved” or “Much improved”: Will continue onsecukinumab 150 mg and will receive secukinumab 150 mg every four weeks,starting at Week 8, until and including Week 48. “Up-titration”: In CGI,“Worse, “No change” or “Minimally improved”, in which up-titration isconsidered appropriate by the investigator: Will receive secukinumab 300mg on Weeks 8, 9, and 12, and then every four weeks until and includingWeek 48. Subjects receiving secukinumab 150 mg and assessed as “Worsechange”, or “Minimally improved” in CGI can be up-titrated tosecukinumab 300 mg at any visit starting at Week 16, if consideredappropriate by the investigator. These subjects will receive secukinumab300 mg at each regular scheduled visit up to Week 48. Once subjectsreceive secukinumab at the dose of 300 mg, there is no reduction back tothe dose of 150 mg. Screening period (Screening to BSL) The screeningperiod of up to 4 weeks will be used to assess eligibility of thesubjects and to taper subjects off disallowed medications. Inductionperiod (BSL to Week 16 pre-dose) The induction period is BSL throughWeek 16 (prior to Week 16 dose). At the start of the induction period,eligible subjects will be entered into the open label treatment group(secukinumab 150 mg, administered subcutaneously). During the inductionperiod, subjects will be visiting the study site at BSL and Weeks 1, 2,3, and 4, and will receive secukinumab 150 mg once weekly for four weeks(BSL and Weeks 1, 2, 3, and 4). Prior to receiving the Week 8 dose, allsubjects in the secukinumab 150 mg group will be assigned to one of twotreatment groups (“up-titration” or “no up-titration”) as explainedabove, and will receive the appropriate secukinumab dose. Assessmentsfor the primary endpoint will be done at Week 16 prior to the dose atWeek 16. In addition, for subjects who discontinue study treatmentprematurely for any reason before the end of the induction period, Week16 (planned End of Induction Period (EOI) must be performedapproximately four weeks after their last dose of study treatment(secukinumab) and then the subject should enter the follow-up period.Subjects receiving secukinumab 150 mg and assessed as “Worse change”, or“Minimally improved” in CGI can be up-titrated to secukinumab 300 mg atany visit starting at Week 16, if considered appropriate by theinvestigator. These subjects will receive secukinumab 300 mg at eachregular scheduled visit up to Week 48. Once subjects receive secukinumabat the dose of 300 mg, there is no reduction back to the dose of 150 mg.Maintenance period (Week 16 post-dose to Week 52) The maintenance periodis defined as Week 16 post-dose through Week 52. During the maintenanceperiod, subjects will be visiting the study site every four weeks,starting at Week 16, up to Week 52, and will receive s.c. studytreatment every four weeks starting at Week 16, and up to Week 48.During the maintenance period, up-titration to 300 mg is permitted atany visit. Down-titration from 300 mg to 150 mg is not permitted. If theinvestigator considers up-titration, the investigator should follow theinstructions as describe above (see induction period). Subjects whofinish the maintenance treatment period will either enter thetreatment-free follow-up period, or may be offered participation in anextension study (if available). In addition, for subjects whodiscontinue study treatment prematurely for any reason before the end ofthe maintenance period, Week 52 (planned End of Maintenance Period (EOM)visit) must be performed approximately four weeks after their last doseof secukinumab, and then the subject should enter the follow-up period.Post-treatment follow-up period (Week 52 to Week 60) Post-treatmentfollow-up visits (no study treatment administered during follow-upperiod) will be at Week 56 (Follow-up visit F4, which is 4 weeks postmaintenance period, but 8 weeks post last dose of secukinumab), and atWeek 60 (Follow-up visit F8 (or End of Post-treatment Follow-up (EOF)),which is 8 weeks post maintenance period, but 12 weeks post last dose ofsecukinumab. Population The study population will consist of male orfemale outpatients or inpatients (≥18 years old) with generalizedpustular psoriasis (GPP). Inpatients are defined as subjects who havebeen admitted to the hospital due to GPP, but not enrolled in this studybefore admission. These subjects may participate in the study. Inclusioncriteria Subjects eligible for inclusion in this study must fulfill allof the following criteria: 1. Subjects must be able to understand andcommunicate with the investigator and comply with the requirements ofthe study and must give a written, signed and dated informed consentbefore any study related activity is performed. Where relevant, a legalrepresentative will also sign the informed study consent according tolocal laws and regulations. 2. Men or women at least 18 years of age attime of screening. 3. At BSL: Presence of GPP classified on the basis ofthe criteria for diagnosis of GPP by Japanese DermatologicalAssociation. Systemic symptoms such as fever and fatigue (subjects inwhom occurrence of systemic symptoms in the past is confirmed can alsobe enrolled). Sterile pustules on erythema spread over the whole body orin wide areas of the body, which can sometimes coalesce into largerlakes of pustules. Histopathologically, forming neutrophilic subcornealpustule characterized by spongiform pustule of Kogoj. 4. At BSL:Erythema area with pustule ≥ 10% Investigational and InvestigationalDrug: reference therapy Secukinumab 150 mg, provided in a 1 mL prefilledsyringe (one syringe for 150 mg dose, two syringes for the 300 mg dose)Efficacy assessments Japanese Dermatological Association (JDA) severityindex for GPP (JDA severity Index for GPP; total score 0-17. Assessmentof skin lesions: area of erythema with pustules, area of erythema, andarea of edema; each score 0-3. Assessment of systemic manifestations andlaboratory findings: fever, WBC count, CRP and serum albumin; each score0-2.) Clinical Global Impression (CGI) Psoriasis Area and Severity Index(PASI; score 0-72) Safety assessments Evaluation of all AEs and SAEsincluding injection site hypersensitivity reactions, vital signs,laboratory assessments and occurrence of infections. Physicalexamination Vital signs Height and weight Laboratory evaluationsHematology Clinical chemistry Urinalysis Immunogenicity (assessment ofanti-secukinumab antibody development) Electrocardiogram (ECG) Pregnancyand assessments of fertility Other assessments Health-Related Quality ofLife (HRQoL) assessments: DLQI SF-36v2 Pharmacokinetics Photography(optional) Data analysis The primary efficacy variable is the proportionof subjects who experience treatment success at Week 16 relative tobaseline (BSL). The analysis of the primary variable will be based onthe FAS.

The clinical trial design for CAIN457A1302 is shown in FIG. 1. Earlyresults from study CAIN457A1302 are shown in FIG. 2. In FIG. 2A it canbe seen that the key symptom of GPP (erythema with pustules) can besignificantly reduced by treatment with secukinumab in the majority ofpatients. In some patients, complete clearance of this symptom isobserved within 3 weeks after starting treatment. At the same time, akey symptom of plaque psoriasis, erythema, is also reduced in themajority of patients (FIG. 2B), but this occurs more slowly and lessfrequently with complete clearance. This shows that erythema as anisolated symptom, such as may occur with plaque-type psoriasis, reactsdifferently from the more typical GPP symptom of erythema with pustules,underscoring the difference between the two diseases and the differencein treatment response. In general, GPP patients' response to secukinumab(1-3 weeks) was faster than plaque-type psoriasis patients' response tosecukinumab (usually 3-4 weeks). Moreover, GPP patients generally didnot need up-titration to 300 mg secukinumab, as 150 mg secukinumab wassufficient to achieve symptom clearance. Both the rapidity and thestrength of secukinumab in treating GPP was surprising compared toplaque-type psoriasis, as GPP is generally considered a more severedisease that plaque-type psoriasis.

Example 2—Study CAIN457A1302-Dose and Dosing Regimen Rationale

Different options for up-titration regimens were explored in model-basedsimulations, regarding their expected impact on concentration levels andclinical response.

The relationship between secukinumab dose/regimen, secukinumabconcentration and the PASI response has previously been modeled using apopulation-PK/PD approach. The model has been built and updatedincrementally with data from patients with moderate-to-severe chronicplaque-type psoriasis from the phase 2 studies CAIN457A2102,CAIN457A2103, CAIN457A2211, CAIN457A2212, and CAIN457A2220.

Concentration profiles of secukinumab are described by a two-compartmentmodel, with combined first-order absorption to reflect subcutaneousadministration and zero-order absorption to reflect intravenousadministration. PASI score profiles are characterized by a turnover(indirect response) model. The drug effect acts on the turnover modelvia an Emax-function, driven by secukinumab concentration in the centralcompartment. Inter-individual variability is estimated as a randomeffect on PK parameters (clearance, volume of distribution,inter-compartmental clearance, volume of distribution of peripheralcompartment, bioavailability, and absorption rate), and PD parameters(turnover out-rate kout, PASI steady state level, and EC₅₀). Modelqualification was performed using standard assessment methods(goodness-of-fit analysis, predictive checks, and external validationbased on prospective predictions).

Based on this model and the final parameter estimates, outcomes for newdosing regimens were simulated. The simulations were performed in orderto design an “up-titration” dosing regimen to address the followingquestion: How can a patient that started with treatment on the 150 mgregimen and that is in need for treatment intensification be up-titratedto 300 mg such that the same exposure level as in a patient starting ona 300 mg regimen is approached rapidly?

The simulation is based on the assumption that the PK and PK/PDrelationships modeled in chronic plaque-type psoriasis are reasonableapproximations of the PK and PK/PD relationships in patients withgeneralized pustular psoriasis. To adjust for a Japanese patientpopulation, a “typical” bodyweight of 70.8 kg (instead of 90 kg as for ageneral psoriasis population) was used.

As shown in FIG. 3, after a starting regimen of 150 mg s.c. at weeks 0,1, 2, 3, 4, the proposed up-titration regimen of 300 mg given at weeks8, 9, and 12 rapidly approaches the same exposure levels as the regimenthat starts with 300 mg doses.

FIG. 4 gives the model-based simulation of PASI75 responder rate for the150 mg regimen, the 300 mg regimen, and the up-titration regimen inmoderate-to-severe chronic plaque-type psoriasis. After up-titration theexpected response is approaching the response levels expected for the300 mg regimen. While the 300 mg PK levels are reached approximately 2weeks after up-titration, the catching-up of clinical response isexpected to reach similar levels after 2-3 months.

This suggests that up-titration to secukinumab 300 mg, and adding oneadditional dose at Week 9, might result in a better response for thosesubjects initially not responding well enough.

In this study, subjects will continue treatment with secukinumab for 52Weeks. This will provide information about long-term efficacy and safetydata pertaining to the subjects with GPP treated with secukinumab.

Example 3—Dosage and Dosing Rationale for Improved Treatment Regimen forPlaque-Type Psoriasis—Up-Titration

To explore options for improved treatment regimens in plaque-typepsoriasis, pharmacokinetic profiles were simulated for up-titration atWeek 12. The simulation is based on the same model as in Example 3(fitted with data from patients with moderate-to-severe chronicplaque-type psoriasis from the phase 2 studies CAIN457A2102,CAIN457A2103, CAIN457A2211, CAIN457A2212, and CAIN457A2220). For thesimulation, a plaque-type psoriasis population was simulated with anaverage bodyweight of about 90 kg and accounting for between-patientdifferences in pharmacokinetic parameters (random effect parameters inthe population-pharmacokinetic model).

FIG. 5 shows the two regimens studied in phase 3 of either 150 mg or 300mg s.c. given at weeks 0, 1, 2, 3, 4, and 8+q4wk as solid and dash-dotline, respectively. For the two explored alternative up-titrationregimens, it can be seen that after a starting regimen of 150 mg s.c. atweeks 0, 1, 2, 3, 4, and 8 an up-titration to 300 mg given at Weeks 12,13, 16+q4wk (dashed line) approaches the exposure levels of the regimenstarting at 300 mg more rapidly than up-titrating at weeks 12, 16+q4wkwithout the dose at week 13 (dotted line).

Example 4—Dosage and Dosing Rationale for Improved Treatment Regimen forPlaque-Type Psoriasis—q6w Maintenance Regimen

To explore options for improved treatment regimens in plaque-typepsoriasis, pharmacokinetic and PASI90 response profiles were simulatedfor down-titration at Week 12 and decreased frequency of dosingbeginning at Week 16. For the pharmacokinetic simulation, a plaque-typepsoriasis population was simulated with an average bodyweight of about90 kg

FIG. 6 shows simulated secukinumab (AIN457) concentration for the tworegimens studied in large phase 3 clinical trials of either 150 mg or300 mg s.c. given at weeks 0, 1, 2, 3, 4, and 8+q4wk as gray-dotted andblack-solid line, respectively. For the explored alternative regimens,it can be seen that after a starting regimen of 300 mg s.c. at weeks 0,1, 2, 3, 4, 8 and 12, a 300 mg q6w maintenance regimen (black-dottedline) will be between the 150 and 300 mg q4w maintenance exposurelevels. Further, down-titration to 150 mg q4w from Week 16 onwards afterstarting with 300 mg sc at Weeks 0, 1, 2, 3, 4, 8 and 12 would lead to acomparable exposure as for the constant 150 mg phase 3 regimen alreadyat Week 28 (gray-solid line).

FIG. 7 shows the simulated PASI90 responder rates for two regimensstudied in large phase 3 clinical trials of either 150 mg or 300 mg s.c.given at weeks 0, 1, 2, 3, 4, and 8+q4wk. For the explored alternativeregimen, it can be seen that after a starting regimen of 300 mg s.c. atweeks 0, 1, 2, 3, 4, 8 and 12, a 300 mg q6w maintenance regimen, as wellas a down titration to 150 mg q4w from Week 16, will lead to PASI90response profiles that are below the responder rates for 300 mg q4w (andabove those for 150 mg q4wk).

Example 5—Pharmokinetic (PK) Information for Seckukinumab

Based on data obtained from various plaque-type psoriasis studies, thefollowing PK information is provided for seckukinumab (Table 6).

TABLE 6 Pharmokinetic values for secukinumab. Experimental PK values arecompiled from various secukinumab psoriasis trials. Simulated values areprovided for the indicated psoriasis dosing regimens. Ex- Inductionperimental mean trough level one month after a 4^(th) dose of 150 mgdelivered s.c. at weeks 0, 1, 2 and 4 ~29.2 μg/mL, with a 30-40%inter-patient variation Maintenance average steady-state trough levels~15 μg/ml (for a monthly [every 4 weeks] 150 mg regimen), with a 30-40%inter- patient variation Simulated Induction (150 or 300 mg delivereds.c. weeks 0, 1, 2, 3, 4, and 8) C_(max) (around 32 days) for a typical90 kg patient: ~52 μg/ml (for 150 mg regimen) ~104 μg/ml (for 300 mgregimen) Maintenance (150 or 300 mg delivered s.c. monthly [every 4weeks] beginning week 12) Average steady-state trough levels for atypical 90 kg psoriasis patient: ~16 μg/ml (for a monthly [every 4weeks] 150 mg regimen) ~33 μg/ml (for a monthly [every 4 weeks] 300 mgregimen) 95% of the population are predicted to be in the range: 5-33μg/ml (for a monthly [every 4 weeks] 150 mg regimen) 11-70 μg/ml (for amonthly [every 4 weeks] 300 mg regimen)

In addition, it has been determined that secukinumab has a T_(max) ofabout 7-8 days, and an elimination half-life of about 30 days. The PKinformation provided in this Example can be used to design differentdosing regimens for treatment of GPP, e.g., delivery of a differentdosage of the IL-17 binding molecule (e.g., an IL-17 antibody, e.g.,secukinumab) from the dosage used in the Examples or delivery of thesame dosage as used in the Examples, but which is provided at adifferent time point from the time points used in the Examples. Bymaintaining the same PK profile, even though a dosing regimen maychange, a skilled artisan is able to use an IL-17 antibody other thansecukinumab for the treatment of GPP.

What is claimed is:
 1. A method of treating palmoplantar pustularpsoriasis (PPP), comprising administering secukinumab to a patient inneed thereof, wherein secukinumab is administered to the patient bysubcutaneous injection at a dose of about 150 mg-about 300 mg at weeks0, 1, 2, 3, and 4, and then every four weeks thereafter.
 2. The methodaccording to claim 1, wherein all doses are about 150 mg or about 300mg.
 3. The method according to claim 1, wherein each dose is about 150mg.
 4. The method according to claim 3, wherein each dose isadministered in a volume of 1 milliliter.
 5. The method according toclaim 1, wherein each dose is about 150 mg, wherein secukinumab isformulated in a pharmaceutical composition comprising a buffer and astabilizer, wherein the pharmaceutical composition is disposed in anautoinjector, and wherein the pharmaceutical composition delivery volumeis 1 milliliter.
 6. The method according to claim 1, wherein each doseis about 150 mg, and wherein secukinumab is disposed in a pre-filledsyringe, a vial, an injection pen, or an autoinjector.
 7. The methodaccording to claim 1, wherein each dose is about 300 mg.
 8. The methodaccording to claim 7, wherein each dose is administered in a volume of 2milliliters.
 9. The method according to claim 1, wherein each dose isabout 300 mg, wherein secukinumab is formulated in a pharmaceuticalcomposition comprising a buffer and a stabilizer, wherein thepharmaceutical composition is disposed in an autoinjector, and whereinthe pharmaceutical composition delivery volume is 2 milliliters.
 10. Themethod according to claim 1, wherein each dose is about 300 mg, andwherein secukinumab is disposed in a pre-filled syringe, a vial, aninjection pen, or an autoinjector.
 11. The method according to claim 1,wherein secukinumab is formulated in a pharmaceutical compositioncomprising a buffer and a stabilizer.
 12. The method according to claim1, further comprising administering to the patient at least oneadditional psoriasis agent.
 13. The method according to claim 12,wherein the at least one additional psoriasis agent is selected from thegroup consisting of ustekinumab, a TNF alpha antagonist, a systemiccorticosteroid, cyclosporin, etretinate, and methotrexate.
 14. Themethod according to claim 1, wherein the method further comprisesadministering to the patient an additional psoriasis agent in an amountat least 50% less than the amount when the psoriasis agent is usedwithout the secukinumab treatment.
 15. The method according to claim 1,wherein the patient has PPP without psoriasis vulgaris.
 16. The methodaccording to claim 1, wherein the patient has PPP with psoriasisvulgaris.